Method for treating postoperative pain and use thereof

Abstract

The present disclosure relates to a method for treating post-hemorrhoidectomy pain and use thereof. The method comprises administering a local anesthetic to a patient in need.

Description

A method for treating postoperative pain and its application

[0001] Cross-reference to related applications

[0002] This application claims priority to Chinese patent application No. 2025101520482, filed on February 11, 2025, which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to the field of biomedicine, and more specifically, to a method for treating postoperative pain and its application. Background Technology

[0004] Hemorrhoids are one of the most common anorectal diseases in clinical practice. Depending on the location, hemorrhoids can be classified as internal hemorrhoids, external hemorrhoids, and mixed hemorrhoids. Treatment methods for hemorrhoids are mainly chosen based on their severity, symptoms, and the patient's specific condition. Generally, they can be divided into two main categories: non-surgical treatment and surgical treatment. When hemorrhoids progress to a severe stage (such as grade III or IV) or when non-surgical treatment is ineffective, surgical treatment is usually considered. Common surgical methods include: hemorrhoidectomy, stapled hemorrhoidopexy, hemorrhoidal artery ligation (HAL), sclerotherapy, and rubber band ligation.

[0005] Postoperative pain is a common complication of hemorrhoid surgery. Most postoperative pain is acute, a normal physiological response to tissue damage or injury, and has physiological significance, serving as a warning of danger or injury. If this pain is not controlled promptly, it can significantly impact the patient's psychological and physiological functions, causing anxiety, insomnia, restlessness, nausea, vomiting, and urinary retention. Furthermore, acute postoperative pain may develop into chronic pain, lasting for six months or even decades, and may even lead to disability. Postoperative pain usually begins after surgery or after the effects of anesthesia wear off, generally lasting 3-7 days, with the first 3 days being the most intense and the critical period for postoperative analgesia. Clinically, it is generally relieved through oral analgesics, topical anesthetic ointments, and warm sitz baths.

[0006] Currently, clinically used analgesics include: opioid analgesics, such as morphine, buprenorphine, tramadol, fentanyl, sufentanil, alfentanil, and remifentanil. These drugs have a rapid onset of action and strong analgesic effect, but a short duration of action and significant side effects. Local anesthetics, such as ropivacaine, lidocaine, bupivacaine, levobupivacaine, procaine, and tetracaine. Nonsteroidal anti-inflammatory drugs (NSAIDs) are divided into two categories: oral and injectable. Oral medications mainly include ibuprofen, meloxicam, celecoxib, lornoxicam, and diclofenac. Injectable medications mainly include parecoxib, lornoxicam, flurbinofen ester, and ketorolac. These drugs are mainly used for postoperative analgesia after minor and medium-sized surgeries. However, for postoperative pain after major surgeries, the analgesic effect of these drugs is not significant and they need to be used in combination with other analgesics (opioids or local anesthetics) to achieve the desired effect. To alleviate postoperative pain in hemorrhoid patients, stabilize organ function, improve prognosis, and shorten hospital stay, analgesia, especially long-acting analgesia, has always been an urgent clinical problem to be solved. Summary of the Invention

[0007] According to one aspect of this disclosure, this disclosure provides a method for treating or preventing postoperative pain, comprising administering to an individual in need a pharmaceutical composition containing ropivacaine crystal A.

[0008] According to one aspect of this disclosure, a pharmaceutical composition for treating or preventing postoperative pain is also provided. The pharmaceutical composition comprises ropivacaine crystals A.

[0009] In some implementations, the aspect ratio of ropivacaine crystal A is approximately 1:1 to 2.

[0010] In some embodiments, at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystal A has an aspect ratio of about 1:(1 to 2).

[0011] In some embodiments, the D of the ropivacaine crystal A 50 It is approximately 5-10 μm.

[0012] In some implementations, the crystal size distribution width (SPAN) value of ropivacaine crystal A is less than 3.

[0013] In some embodiments, at least 95% of the crystal grain size distribution width (SPAN) values ​​in the ropivacaine crystal A are approximately 1 to 2.

[0014] In some embodiments, at least 80%, 85%, 90%, and 95% of the ropivacaine crystals A have a crystal size distribution width (SPAN) value of about 1 to 2.

[0015] [Correction 17.09.2026 according to Rule 91] In some embodiments, ropivacaine crystal A has the particle morphology shown in FIG2.

[0016] In some embodiments, the ropivacaine crystal A has the XRPD diffraction peaks shown in Figure 1.

[0017] According to one aspect of this disclosure, the method disclosed herein is used to treat or prevent pain caused by hemorrhoid surgery.

[0018] In some implementation schemes, postoperative pain includes traumatic pain, chemical pain, neuropathic pain, and inflammatory pain.

[0019] In some implementations, postoperative pain includes acute pain and / or chronic pain.

[0020] In some implementations, treatment or prevention includes reducing, suppressing, reversing, slowing down, or stopping the progression or severity of an existing condition, disease, symptom, or illness.

[0021] In some implementations, treatment or prevention includes the cure, relief, reduction, or elimination of the progression or severity of a disease, condition, symptom, or illness.

[0022] According to one aspect of this disclosure, in the method of this disclosure, ropivacaine crystal A is administered to an individual in need by injection.

[0023] In some implementations, ropivacaine crystal A is administered by perianal injection to the individual in need.

[0024] In some embodiments, the method disclosed herein includes applying a pharmaceutical composition topically to the perianal area.

[0025] In some embodiments, the method disclosed herein includes applying a pharmaceutical composition to the edge of the anus.

[0026] In some embodiments, the method disclosed herein includes applying a pharmaceutical composition to the peripheral nerve site at the anal end.

[0027] In some embodiments, the method disclosed herein includes applying the pharmaceutical composition to the anal margin at a depth of 0.5-3 cm.

[0028] In some embodiments, the method disclosed herein includes injecting a pharmaceutical composition into the perianal anal sphincter and subcutaneous tissue.

[0029] According to one aspect of this disclosure, this disclosure provides a method for injecting and administering a pharmaceutical composition for postoperative analgesia to an individual in need, comprising:

[0030] Select the entry point of the injection needle on the patient's body, including the selection of the injection point and direction;

[0031] Insert the injection needle into the patient at the entry point;

[0032] The pharmaceutical composition is administered topically to an individual in need via an injection needle. The pharmaceutical composition may include saline solution and an active pharmaceutical ingredient, such as ropivacaine crystals A.

[0033] In some implementations, the injection needle is selected to have at least four entry points, such as four to eight points, preferably four, five, six, seven, or eight points.

[0034] In some implementation schemes, the four points are located at the rock cutting positions of 3, 6, 9, and 12 o'clock.

[0035] According to one aspect of this disclosure, this disclosure provides a method for administering a pharmaceutical composition for postoperative analgesia to the peripheral nerves of an individual in need, comprising: selecting an entry point for an injection needle around the anus of the individual in need, such as a human patient; and inserting the injection needle into the individual in need from the selected point.

[0036] The injection needle is selected with at least 4 entry points; for example, 4-8 points, preferably 4, 5, 6, 7 or 8 points.

[0037] In some implementation schemes, the four points are located at the rock cutting positions of 3, 6, 9, and 12 o'clock.

[0038] An effective therapeutic dose of the drug composition, comprising ropivacaine crystals A, is injected locally into the perianal area of ​​the individual in need via an injection needle. Prior to use, the drug composition is prepared into an injectable form using sterile water for injection and normal saline. Free ropivacaine, as an amide-type local anesthetic, inhibits impulse transmission in peripheral sensory nerves, providing postoperative analgesia to the patient.

[0039] According to one aspect of this disclosure, a method is provided for administering a pharmaceutical composition for postoperative analgesia to the perianal region of a human patient, comprising:

[0040] Choose the injection point around the patient's anus.

[0041] The needle tip is advanced into the anal sphincter along a path from the injection point to the patient's sphincter plane.

[0042] A therapeutically effective amount of the pharmaceutical composition is administered to the local area via an injection needle while the needle is withdrawn. The pharmaceutical composition includes ropivacaine crystal A, thereby administering a pharmaceutical composition for postoperative analgesia to the perianal region of a human patient.

[0043] According to one aspect of this disclosure, this disclosure provides a method for treating postoperative pain in patients after hemorrhoidectomy, including:

[0044] Choose the injection point around the anus for the individual in need;

[0045] Choose at least 4 points; for example, 4-8 points, preferably 4, 5, 6, 7 or 8 points.

[0046] Insert the injection needle into the patient's body at the selected point;

[0047] The pharmaceutical composition, comprising ropivacaine crystal A, is injected locally into the perianal area of ​​an individual in need via an injection needle into the perianal region.

[0048] According to one aspect of this disclosure, this disclosure provides a method for administering local infiltration of a perianal anesthetic to an individual in need to relieve anal pain after hemorrhoidectomy, comprising:

[0049] Choose the injection point around the anus for the individual in need;

[0050] Select at least 4 injection points, including injection points 0.5-3cm from the anal verge, and at the 3 o'clock, 6 o'clock, 9 o'clock, and 12 o'clock positions in the lithotomy position;

[0051] The injection needle is inserted into the individual in need at the selected point;

[0052] The pharmaceutical composition, comprising ropivacaine crystal A, is injected locally into the perianal area of ​​an individual in need via an injection needle into the perianal region.

[0053] In some embodiments, the method of this disclosure includes the local infiltration and application of a pharmaceutical composition around the anus of a patient.

[0054] In some embodiments, the method disclosed herein includes applying a pharmaceutical composition to the edge of the anus.

[0055] In some embodiments, the method of this disclosure includes applying the pharmaceutical composition to the anal margin at a depth of 0.5-3 cm, selecting at least 4 points for injection of the pharmaceutical composition.

[0056] In some implementations, the injection needle is a 21G needle, or a similar specification, and other commonly used injection needles capable of local administration of medication in the perianal region, with a needle length between 30mm and 40mm.

[0057] In some implementations, the injection needle is not sealed.

[0058] In some implementations, the injection needle is inserted around the anus of the individual in need to a depth of more than 3 cm.

[0059] In some implementations, the pharmaceutical composition is applied via local infiltration around the anus.

[0060] In some implementations, the drug composition is injected at at least four points selected 0.5-3 cm from the anal margin.

[0061] In some implementations, with the patient in the lithotomy position, 4 mL of the drug composition is injected subcutaneously into the space between the anal sphincter and the anal sphincter using a 21G needle inserted vertically at the 6 o'clock position, 0.5-3 cm from the anal margin, while withdrawing the needle.

[0062] In some implementations, with the patient in the lithotomy position, 4 mL of the drug composition is injected subcutaneously into the space between the anal sphincter and the anal sphincter using a 21G needle inserted vertically at the 12 o'clock position, 0.5-3 cm from the anal margin, with the needle withdrawn while injecting.

[0063] In some implementations, with the patient in the lithotomy position, 2 mL of the drug composition is injected subcutaneously into the space between the anal sphincter and the anal sphincter plane using a 21G needle inserted vertically at the 3 o'clock position, 0.5-3 cm from the anal margin.

[0064] In some implementations, with the patient in the lithotomy position, 2 mL of the drug composition is injected subcutaneously into the space between the anal sphincter and the 3 o'clock position using a 21G needle inserted downwards at a 45° angle at a distance of 0.5-3 cm from the anal margin.

[0065] In some implementations, with the patient in the lithotomy position, 2 mL of the drug composition is injected subcutaneously into the space between the anal sphincter and the 3 o'clock position using a 21G needle inserted at a 45° angle upwards at a distance of 0.5-3 cm from the anal margin.

[0066] In some implementations, with the patient in the lithotomy position, 2 mL of the drug composition is injected subcutaneously into the space between the anal sphincter and the anal sphincter plane using a 21G needle inserted vertically at the 9 o'clock position, 0.5-3 cm from the anal margin.

[0067] In some implementations, with the patient in the lithotomy position, 2 mL of the drug composition is injected subcutaneously into the space between the anal sphincter and the 9 o'clock position using a 21G needle inserted downwards at a 45° angle at a distance of 0.5-3 cm from the anal margin.

[0068] In some implementations, with the patient in the lithotomy position, 2 mL of the drug composition is injected subcutaneously into the space between the anal sphincter and the 9 o'clock position at an angle of 45° upwards using a 21G needle at a distance of 0.5-3 cm from the anal margin.

[0069] In some implementations, 10 mL of the drug composition is locally infiltrated into the anal sphincter and subcutaneous tissue using a 21G needle at the edge of the surgical incision.

[0070] In some embodiments of this disclosure, the pharmaceutical composition is administered by injection.

[0071] In some embodiments of this disclosure, the pharmaceutical composition refers to a composition in a suitable form of administration. A suitable form of administration depends on the intended use or route of entry (including, but not limited to, subcutaneous injection), single injection, continuous injection, indwelling catheter, and continuous infusion.

[0072] In some embodiments of this disclosure, the amount of the pharmaceutical composition used for a single injection does not exceed 6 mL, preferably 5 mL, 4 mL, 3 mL, or 2 mL.

[0073] In some embodiments of this disclosure, methods for treating or preventing postoperative pain include injecting approximately 30 mL of a pharmaceutical composition into an individual in need.

[0074] In some embodiments of this disclosure, the pharmaceutical composition is a liquid composition, emulsion, suspension, or dry preparation.

[0075] In some embodiments of this disclosure, the pharmaceutical composition further comprises any one or any combination thereof selected from thickeners, surfactants, fillers.

[0076] In some embodiments of this disclosure, the efficacy of high-dose ropivacaine crystal A exceeds that of low-dose ropivacaine crystal A.

[0077] In some embodiments of this disclosure, the lower dose is between 200 mg and 400 mg.

[0078] In some embodiments of this disclosure, higher doses are between 400 mg and 600 g.

[0079] In some embodiments of this disclosure, the dosage may be selected between 200 mg and 800 mg, preferably 200 mg-750 mg, 200 mg-700 mg, 200 mg-650 mg, 200 mg-600 mg, 200 mg-550 mg, 200 mg-500 mg, 200 mg-450 mg, 200 mg-400 mg, 200 mg-350 mg, 200 mg-300 mg, 200 mg-250 mg, 350 mg-650 mg, 400 mg-600 mg, 450 mg-550 mg, or 500 mg-600 mg.

[0080] According to one aspect of this disclosure, a pharmaceutical composition for the prevention or treatment of postoperative pain can be used in combination with other anesthetics or other analgesics, or together with other anesthetics or other analgesics in an anesthesia or analgesia regimen. The pharmaceutical composition contains ropivacaine crystals A.

[0081] Other anesthetic agents include general anesthetics and local anesthetics (such as spinal anesthetics). General anesthetics include, but are not limited to, etomidate, ketamine, ciprofol, propofol, and thiopental sodium. Local anesthetics include, but are not limited to, benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, propoxycaine, procaine, amethocaine, articaine, bupivacaine, eticaine, levobupivacaine, lidocaine, mepivacaine, and trimecaine.

[0082] Examples of adjunctive anesthetic drugs include, but are not limited to, midazolam and diazepam.

[0083] Examples of other analgesics include opioid analgesics and non-opioid analgesics. Non-opioid analgesics include antipyretic analgesics and anti-inflammatory drugs, adjunctive analgesics, etc.

[0084] In some implementations, opioid analgesics include, but are not limited to, hydrocodone, dextropropoxyphene, codeine, dihydrocodeine, tramadol, morphine, oxycodone, hydromorphone, fentanyl, sufentanil, remifentanil, buprenorphine, pethidine, nalbuphine, methadone, levorphanol, pentazocine, or naloxone.

[0085] In some implementations, the antipyretic analgesic is selected from: acetaminophen, NSAIDs (preferably selective COX-2 inhibitors (e.g., celecoxib) or non-selective inhibitors (e.g., ibuprofen, aspirin, diclofenac, naproxen)).

[0086] In some implementations, the adjunctive analgesic is selected from: anticonvulsants (e.g., gabapentin), tricyclic antidepressants (e.g., amitriptyline), psychotropic drugs, NMDA receptor antagonists (e.g., ketamine), α2-adrenergic receptor agonists (e.g., dexmedetomidine), and glucocorticoids (e.g., dexamethasone).

[0087] In some embodiments of this disclosure, ropivacaine crystal A is used simultaneously, sequentially, or in sequence with other anesthetics or other analgesics.

[0088] According to one aspect of this disclosure, a method for preparing ropivacaine crystal A is also provided. The method includes:

[0089] Ropivacaine hydrochloride was dissolved in a solvent under stirring at room temperature. After complete dissolution, sodium hydroxide solution was added to adjust the pH to alkaline. The solution was then heated to 90°C–100°C, and the mixture was sheared and dispersed while heating for at least 20 minutes. The solution was filtered to obtain the target crystals. The solvent can be water. The reaction temperature for the dissolution step was below 40°C, preferably room temperature. The pH adjustment step refers to adjusting the pH value to be greater than 7.

[0090] In some embodiments, the crystal size distribution width (SPAN) value of the ropivacaine crystal A prepared in this disclosure is less than 3, as determined by testing.

[0091] In some embodiments, it has been determined that at least 95% of the crystal grain size distribution width (SPAN) values ​​in the ropivacaine crystal A prepared in this disclosure are approximately 1 to 2.

[0092] In some embodiments, it has been determined that at least 80%, 85%, 90%, and 95% of the ropivacaine crystals A prepared in this disclosure have a crystal size distribution width (SPAN) value of approximately 1 to 2.

[0093] In some embodiments, the aspect ratio of the ropivacaine crystal A prepared in this disclosure is approximately 1:1 to 2, as determined by testing.

[0094] In some embodiments, the ropivacaine crystal A prepared according to this disclosure has XRPD diffraction peaks at 8.894, 10.485, 13.045, 13.580, 14.300, 16.348, 17.918, 19.122, 19.470, 19.984, 20.315, 21.107, 22.567, 23.529, 24.459, 25.593, 26.309, 31.295, 31.880, and 32.449, as detected.

[0095] In some embodiments, the ropivacaine crystal A prepared according to this disclosure is found to have XRPD diffraction peaks as shown in Figure 1.

[0096] According to one aspect of this disclosure, the disclosure also provides the use of ropivacaine crystal A in the preparation of a medicament for treating postoperative pain.

[0097] In one implementation, the postoperative pain includes postoperative pain from hemorrhoid treatment.

[0098] In one embodiment, the drug is administered to the patient via local injection.

[0099] In one embodiment, the drug is administered to the patient via local infiltration. This local infiltration has all the features described in the foregoing treatment methods.

[0100] In one embodiment, the drug can be formulated into any pharmaceutical composition suitable for injection administration. The pharmaceutical composition has all the features described in the foregoing treatment methods.

[0101] By applying the disclosed ropivacaine crystal A via perianal local infiltration, a prolonged and sustained analgesic effect can be produced, demonstrating significant advantages. Ropivacaine crystal A sustains the release of its active ingredient, enabling postoperative pain control for up to 72 hours, approximately seven times longer than the duration of action of conventional ropivacaine (10 hours or less). Furthermore, the prolonged analgesic effect significantly reduces the amount of opioid analgesics used, providing patients with more satisfactory analgesia.

[0102] Furthermore, the methods disclosed herein produce excellent analgesic effects, thus requiring fewer rescue analgesics or eliminating the need for opioids to manage postoperative pain. In some protocols, even multimodal analgesia is unnecessary. In some protocol examples, the methods described herein produce unexpectedly good results, making postoperative rescue analgesia solely dependent on opioids. Attached Figure Description

[0103] Figure 1: X-ray diffraction pattern of ropivacaine crystal A.

[0104] Figure 2: Microcrystalline morphology diagram of Example 1.

[0105] Figure 3: Overlay curve of time-resting pain intensity scores.

[0106] Figure 4: Overlay of mean blood drug concentration-time curves for each group of subjects. Detailed Implementation

[0107] definition:

[0108] As used in this article, the term "pain" refers to a physiological and / or psychological reaction or response to a potential or actual stimulus that may result in tissue damage, injury, disease, or other conditions. Types of pain include, but are not limited to, acute pain, chronic pain, thermal pain, traumatic pain, chemical pain, inflammatory pain, ischemic pain, dull pain, sharp pain, stabbing pain, visceral pain, and neuropathic pain.

[0109] Unless otherwise indicated, the compounds disclosed herein, in addition to their specific structures, may also be interpreted as pharmaceutically acceptable salts of the compound, their stereoisomers, isotopic isomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites, i.e., pharmaceutically acceptable salts of the compound, their stereoisomers, isotopic isomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compound.

[0110] The term "treatment" refers to medical care given to any subject in need. The treatment may be preventative, palliative, symptomatic, and / or curative. The duration and purpose of the treatment may vary between individuals depending on the subject's condition and health.

[0111] The term "treatment or prevention" refers to reducing, inhibiting, reversing, slowing down, or stopping the progression or severity of an existing condition, disease, symptom, or illness. This includes, but is not limited to, curing, alleviating, reducing, or eliminating the progression or severity of an existing disease, condition, symptom, or illness.

[0112] Unless otherwise specified, the quantities of different components and reaction conditions used herein are to be interpreted as "approximate" or "about". Accordingly, unless otherwise specified, the numerical parameters cited below and in the claims are approximate parameters, and different numerical parameters may be obtained under their respective experimental conditions due to different standard errors.

[0113] As used in this article, "individual in need" means a mammal with a condition, disease, ailment or symptom that requires treatment or prevention, preferably a human, but may also be a non-human animal, including non-human primates (e.g., monkeys, cynomolgus monkeys, etc.), pets (e.g., cats, dogs, etc.), livestock (e.g., cattle, sheep, pigs, horses, etc.) and rodents (e.g., rats, mice, guinea pigs, etc.).

[0114] The term "subject" refers to people and animals (such as mammals), including but not limited to humans, non-human primates, rodents, etc., who will become recipients of a specific treatment.

[0115] In general, the terms "subject" and "patient" are used interchangeably here when referring to human subjects.

[0116] In this article, the terms "subject" and "individual in need" have the same meaning and can be used interchangeably.

[0117] As used herein, "effective amount" means the amount, concentration, or dose of one or more of the disclosed compounds or their pharmaceutically acceptable salts that, after being administered in a single or multiple doses to an individual in need, provide the desired effect (i.e., produce a clinically measurable difference in the individual's condition, such as a reduction in pain sensation) in the diagnosed or treated individual. An effective amount can be readily determined by those skilled in the art using known techniques and by observing results obtained under similar conditions. In determining the effective amount for an individual, many factors are considered, including but not limited to the mammalian species, body size, age, general health status, the specific disease or condition involved, the severity of the disease or condition, the individual's response, the specific compound administered, the mode of administration, the bioavailability characteristics of the administered formulation, the selected dosing regimen, the use of concomitant drug treatments, and other relevant circumstances.

[0118] The term "effective therapeutic dose" refers to ropivacaine or its salts, such as ropivacaine, in the pharmaceutical compositions described herein, meaning that ropivacaine crystal A is released in a manner sufficient to achieve a specific level of anesthetic effect. The specific dose will vary depending on the particular anesthetic agent and factors such as the patient's age, sex, general condition, and body size. Those skilled in the art can readily take these factors into account and use them to determine the optimal therapeutic concentration without requiring extensive experimentation.

[0119] The term "single injection dose" refers to the amount of ropivacaine crystal A administered at each injection site. For injection administration, it means the amount of the drug composition administered in a single dose, such as 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, or 6 mL.

[0120] The term "unit dose" refers to the amount of active ingredient contained in a unit dosage form. For example, for injectable preparations, it usually refers to the amount of active ingredient contained in each ampoule, such as 800mg, 700mg, 600mg, 500mg, 400mg, 300mg, 200mg, etc.

[0121] The term "local infiltration" refers to the direct injection of an anesthetic into the skin and deeper tissues (such as subcutaneous tissue and muscle layer), causing temporary loss of sensation in the nerve endings of the injection area. In treating hemorrhoids, doctors often use local infiltration anesthesia around the anus to ensure a painless procedure, especially during procedures such as surgical removal of hemorrhoids or sclerotherapy.

[0122] The pharmaceutical compositions disclosed herein can be administered regionally or locally. "Regional" or "local" anesthesia, as used herein, differs from general anesthesia and refers to a route of administration that allows preferential delivery of the anesthetic to a specific area of ​​the body, such as near a nerve or nerve bundle. In contrast, general anesthesia allows for systemic administration, such as via intravenous infusion. Regional or local anesthesia typically allows the administration of a lower systemic concentration (although the local concentration may be higher) of the anesthetic to a subject to relieve pain or reduce pain sensation in at least a portion of the subject's body.

[0123] The term "lithotomy position" refers to the most commonly used position for anal surgery. The patient lies supine on the examination bed with their buttocks close to the edge of the bed and placed on a leg rest. This position maximizes the exposure of the perineum and is commonly used for rectal and anal canal surgeries as well as gynecological examinations.

[0124] In this disclosure, "particle size" specifically refers to the particle size of a suspension after ultrasonic disruption and dispersion treatment (under a microscope, the suspended particles appear dispersed into individual crystals). If the suspension is not dispersed and the particle size is measured directly, the crystals will have varying degrees of aggregation, and the measured particle size cannot represent the true size of the crystals.

[0125] In this disclosure, the particle size distribution width (SPAN) is an index characterizing the crystal distribution width, calculated by the following formula: SPAN = (D90 - D10) / D50.

[0126] In this disclosure, the definition of efficacy is consistent with the understanding in the art. In some embodiments of this disclosure, efficacy is defined as any improvement in the results monitored in the studies described herein.

[0127] Example 1: Preparation of Ropivacaine Crystal A

[0128] Weigh an appropriate amount of ropivacaine hydrochloride, add water, and stir to dissolve at room temperature. After complete dissolution, add sodium hydroxide solution to adjust the pH to >9. Then heat the solution to 90℃~100℃, and disperse it by shearing while heating. After holding at 90℃ for 60 minutes, take samples to detect changes in single crystal size and crystal clusters during the heating process.

[0129] Particle size determination method: Mix 2 ml of drug solution with 6 ml of 0.1% Tween 80 in a vial, mix well, disperse using a Sonics VCX150 ultrasonic disruptor, and then add a dispersant with an optical concentration of 5%–10% for measurement. The ultrasonic disruption parameters are as follows: power 25%, ultrasonic for 10 seconds with a 5-second pause, and a total ultrasonic time of 10 minutes.

[0130] Results: See Figure 1, SPAN = 1.1-1.2.

[0131] Example 2: Analgesic Effect Test

[0132] This trial compared the postoperative analgesic effects of a single injection of ropivacaine crystal A and ropivacaine hydrochloride when administering local infiltration analgesia to subjects undergoing hemorrhoidectomy.

[0133] 1. Subjects

[0134] 1.1 Subject inclusion criteria

[0135] Subjects must understand the procedures and methods of this clinical trial (including the pain intensity assessment method), obtain full informed consent, voluntarily participate, and have their informed consent form signed by themselves or their legal guardians.

[0136] Males or females aged 18 years or older; Body Mass Index (BMI) between 18.0 and 30.0 kg / m² 2 Within the range (including critical values).

[0137] Subjects with grade III-IV internal or external hemorrhoids, or mixed hemorrhoids with prolapse, are scheduled to undergo external stripping and internal ligation under general anesthesia, with a cumulative skin incision length ≥3cm.

[0138] Subjects classified as ASA I-III.

[0139] Female or male subjects of childbearing age must agree to use effective contraception for themselves and their male partners for 30 days after signing the informed consent form and after using the investigational drug.

[0140] 1.2 Exclusion criteria for subjects

[0141] ① Individuals with a history of allergy or idiopathic reaction to amide-type local anesthetics, opioids, or any component of the drugs used in this study, or individuals with an allergic constitution (such as allergies to two or more drugs, foods, or pollen).

[0142] ② Those with significantly prolonged QTc interval, or those with other risk factors that lead to torsades de pointes (TdP) (such as heart failure, hypokalemia, hypomagnesemia, bradycardia, hereditary long QT syndrome), or those who are currently using medications that prolong the QT / QTc interval.

[0143] ③ Pain unrelated to hemorrhoidectomy (e.g., rheumatoid arthritis, chronic neuropathic pain, or associated vasectomy) or surgical complications may confuse postoperative pain assessors.

[0144] ④ Subjects with a history of hemorrhoidectomy.

[0145] ⑤ Comorbid fecal incontinence, perianal abscess, anal fissure, rectal prolapse, portal hypertension with rectal varicose veins, and inflammatory bowel disease, etc.

[0146] ⑥ Individuals with a history of or currently suffering from any of the following serious clinical conditions: ① Respiratory system diseases: such as acute or bronchial asthma, pulmonary heart disease, other chronic lung diseases, or a history of respiratory depression; ② Neuropsychiatric diseases: such as traumatic brain injury, increased intracranial pressure, depression, anxiety, epilepsy (including a history of febrile seizures in childhood), other brain diseases or mental disorders that affect self-assessment; ③ Circulatory system diseases: such as unstable angina and / or myocardial infarction within the past 6 months, heart failure (NYHA class III-IV) or poorly controlled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥90 mmHg); ④ Hematologic system diseases: bleeding disorders caused by coagulation factor defects or other coagulation marker disorders; ⑤ Digestive system diseases: such as known gastrointestinal bleeding, gastrointestinal obstruction or perforation, and other diseases that may cause danger to the gastrointestinal tract; ⑥ Individuals with other diseases or a history of diseases that may significantly affect the safety evaluation or in vivo metabolism of the investigational drug.

[0147] ⑦ Vomiting during the screening period, or a history of severe or refractory postoperative nausea or vomiting.

[0148] ⑧ During the screening period, laboratory test results must meet the following requirements: ① Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 times the upper limit of normal; ② Serum creatinine (Cr) ≥ 1.5 times the upper limit of normal; ③ Creatinine clearance rate < 50 mL / min (using the Cockcroft-Gault formula); ④ Fasting venous blood glucose > 7.8 mmol / L; ⑤ Prothrombin time (PT) > upper limit of normal + 3s or activated partial thromboplastin time (APTT) > upper limit of normal + 10s.

[0149] ⑨ Patients who have used or are currently using the following medications or treatments within a certain period prior to surgery: a. Anticonvulsants, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, antipsychotics, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors (SNRIs), muscle relaxants, and anticholinergics within 2 weeks prior to surgery; b. Opioids or opioids within 2 weeks prior to surgery; c. Within 5 half-lives or 10 days prior to surgery (whichever is longer). (d) Use of systemic steroids (excluding inhaled topical steroids) within 72 hours before the end of the administration; (e) Use of local anesthetics within 72 hours before surgery; (f) Use of any analgesics not specified in the regimen (such as nonsteroidal anti-inflammatory drugs (excluding low-dose cardioprotective aspirin), oxycodone, ketoprofen, diclofenac, or pregabalin, etc.) within 12 hours before surgery and 72 hours after the end of the administration; (c) Intravenous or oral metronidazole within 3 days before surgery.

[0150] ⑩ Patients who cannot quit smoking or drinking alcohol (except for treatment drugs containing alcohol) from 48 hours before surgery to 72 hours after the end of medication.

[0151] Those who regularly drink alcohol within the three months (90 days) prior to screening, i.e., those who drink more than 14 units of alcohol per week (1 unit = 360 mL of beer or 45 mL of spirits with an alcohol content of 40% or 150 mL of wine).

[0152] Those who have undergone major surgery or surgery that may significantly affect the in vivo process or safety evaluation of the investigational drug within 3 months (90 days) prior to screening are eligible for screening.

[0153] Those who participated in a drug or device clinical trial and received treatment with the investigational drug or device within 3 months (90 days) prior to screening.

[0154] Those with a history of fainting from needles or blood, or those who cannot tolerate intravenous puncture for blood collection.

[0155] Those with a history of drug abuse within the two years prior to screening.

[0156] A positive blood or urine pregnancy test during the screening period, or being in the breastfeeding period, or currently not having breast milk but less than 6 months postpartum.

[0157] Researchers believe that individuals unsuitable for participation in this trial include those who would be unable to evaluate efficacy or are unlikely to complete the expected treatment course and follow-up.

[0158] 2. Experimental Design and Procedure

[0159] This was a phase 2, multicenter, randomized, double-blind, positive-controlled study. Twenty-four participants scheduled for hemorrhoidectomy were enrolled to collect efficacy, safety, and pharmacokinetic (PK) data. Participants received a single dose of either ropivacaine crystal A 600mg or ropivacaine hydrochloride 75mg perianal infiltration. Participants were randomly assigned to either the ropivacaine crystal A 600mg intervention group or the ropivacaine hydrochloride 75mg intervention group.

[0160] The trial lasted approximately 18 days, divided into a screening period and an observation period. The screening period lasted 2 weeks, and the observation period lasted 4 days (patients were discharged after 72 hours of continuous analgesia observation following drug administration).

[0161] Table 1: Subjects

[0162] 2.1 Screening period (D-14 to D-1)

[0163] From day -14 to day -1, after the subjects voluntarily sign a written informed consent form, the inclusion and exclusion criteria must be screened to confirm whether the subjects meet the trial participation conditions.

[0164] 2.2 Observation period (D1-D4)

[0165] Before the trial, communicate with the subjects about clinical trial drug administration and NRS pain intensity scoring training (if applicable). On day 1, the subjects will undergo hemorrhoidectomy under general anesthesia. After the surgery (skin suturing is completed), administer a single local infiltration test drug. The subjects will be discharged from the group after a safety check 72 hours after the completion of the drug administration.

[0166] The start and stop times of the surgery, as well as other surgical details (including the length of the surgical incision), should be recorded in the eCRF. The subject will receive the study drug unless he / she experiences a major clinical event during the surgery that could destabilize his / her condition or complicate the postoperative process (such as excessive bleeding or hemodynamic instability). After the surgery is completed (skin suturing is finished), the study drug will be administered via local infiltration. For complete details on the study drug administration technique, please refer to the administration manual. The start and stop times of the study drug administration will be recorded in the eCRF.

[0167] Note: For all efficacy, safety assessments and PK collections, the end time of study drug administration will be considered as 0h. Concomitant medications used during surgery will be recorded (note that intravenous infusions and oxygen are not required unless used to treat adverse events).

[0168] Subjects will remain in the hospital for observation for at least 72 hours after receiving the study drug. Subjects will be discharged 72 hours after the drug administration ends and after completing a safety check. The study process and assessment are listed below.

[0169] NRS pain intensity score:

[0170] Resting and movement (cough) pain scoring time points: within 1 hour before surgery, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours after administration (time window ± 15 min), and 36 hours, 48 ​​hours, 60 hours, and 72 hours (time window ± 1 hour); resting pain scoring was completed before movement scoring, and subjects should be in a resting position (supine or supine) for at least 5 minutes before resting pain assessment.

[0171] Perform resting and exercise assessments before administering remedial analgesics.

[0172] Pain intensity was assessed after each dressing change or defecation. Resting and exercise pain intensity were not assessed within 60 minutes after the dressing change or defecation. Rescue analgesics were administered to the subjects during dressing changes or defecation. Pain intensity was assessed only during dressing changes or defecation before administering rescue analgesics (resting and exercise scores were not required).

[0173] The use of remedial analgesics;

[0174] Vital signs: 12h, 24h (time window ±15min) and 48h, 72h (time window ±1h) after the end of drug administration;

[0175] 12-lead electrocardiogram: ECG monitoring was performed within 2 hours after drug administration and an examination was performed 72 hours after drug administration (after discharge of the group, no time window was set);

[0176] PK blood sample collection: 15 min after drug administration (time window ±2 min), 1 h, 4 h, 8 h, 12 h, 24 h (time window ±15 min), and 48 h and 72 h (time window ±1 h);

[0177] Physical examination: 72h±2h after the end of drug administration;

[0178] Complete blood count (CBC) test;

[0179] Urinalysis;

[0180] Blood biochemistry tests;

[0181] Routine coagulation tests;

[0182] Blood / urine pregnancy test: only applicable to women of childbearing age;

[0183] Analgesia satisfaction of subjects 72 hours after administration;

[0184] Accompanying medication records;

[0185] Security information monitoring.

[0186] 3. Administration method

[0187] Subject D1 will undergo hemorrhoidectomy under general anesthesia. After the surgery (skin suturing is completed), a single local infiltration test will be performed.

[0188] 3.1 Drug Preparation

[0189] Ropivacaine drug preparation:

[0190] Aspirate the medication: Take one vial of ropivacaine injection and aspirate 7.5 mL of the medication into the syringe using a 30 mL syringe;

[0191] Diluting the medication: Draw 0.9% sodium chloride injection solution into the syringe from the previous step and dilute the medication to 30mL. Gently shake to mix thoroughly. Replace the prepared syringe with an 8-gauge injection needle.

[0192] Place in a sterile tray for later use.

[0193] Preparation of Ropivacaine Crystal A for Injection:

[0194] Preparation of sterile water for injection: Take 3 5mL syringes and draw 4mL of sterile water for injection into each syringe.

[0195] Preparation of 0.9% sodium chloride injection: Take one 30mL syringe and draw 18mL of 0.9% sodium chloride injection;

[0196] Test drug re-suspension: Take 3 bottles of test drug, slowly inject 3 4mL vials of sterile water for injection along the inner wall of the bottle, and gently shake to fully dissolve the drug;

[0197] Aspirate the drug solution: Take a 30mL syringe and aspirate the entire compound suspension from step [3], gently shake it by hand to mix it evenly;

[0198] Rinse the medicine bottles: Slowly pour the prepared 18mL of 0.9% sodium chloride injection solution along the inner wall of each of the three bottles, and gently shake.

[0199] Rinse off any remaining medication, and draw the rinse solution completely into the syringe in step [4]. Gently shake the syringe to mix it thoroughly.

[0200] Replace the prepared syringe with an 8-gauge injection needle.

[0201] Place in a sterile tray for later use.

[0202] Key points for configuration operation:

[0203] During the operation, aseptic techniques and verification procedures were strictly followed. Used disposable syringes, 0.9% sodium chloride injection solution and sterile water for injection packaging, discarded drugs and other medical waste were disposed of in strict accordance with the research center's medical waste regulations. Used experimental drug packaging and boxes were collected by the drug administrator, stored in a designated area, and relevant information was recorded and confirmed by signature.

[0204] The reviewer reviews the entire configuration process and records relevant configuration information during the process (including but not limited to configuration start / end time, configuration ambient temperature, etc.). After the operation is completed, the operator confirms the configuration information and signs it.

[0205] The test drug should be prepared at room temperature and should be used within 2 hours after preparation.

[0206] Syringes should be used by designated personnel for designated medications only and should not be used interchangeably.

[0207] To minimize operational deviations during drug preparation, one to two people should be assigned to drug preparation as much as possible during the experiment to ensure consistency in operation.

[0208] During the preparation process, do not shake vigorously to avoid generating air bubbles in the solution.

[0209] 3.2 Drug administration procedure

[0210] 3.2.1 Exhaust air: Expel all air from the syringe until a droplet appears at the needle tip, and record the actual volume of the medication to be used in each syringe.

[0211] 3.2.2 Local infiltration injection:

[0212] a) Needle insertion points: Insert the needle at the 3 o'clock, 6 o'clock, 9 o'clock and 12 o'clock positions, about 0.5-3 cm from the anal verge.

[0213] b) Needle insertion angle:

[0214] i. Insert the needle vertically into the ischiorectal fossa at the 12 o'clock and 6 o'clock positions.

[0215] ii. Insert the needle vertically at the 3 o'clock and 9 o'clock positions, at a downward 45° angle and an upward 45° angle, with a needle depth greater than 3cm.

[0216] 3.2.3 Dosage volume (30 mL):

[0217] a) At 12 o'clock and 6 o'clock, administer approximately 4 mL of medication while withdrawing the needle.

[0218] b) At the 3 o'clock and 9 o'clock positions, while withdrawing the needle, administer the medication. Inject approximately 2 mL of medication in each direction.

[0219] 3.2.4 Infiltrate the surgical wound with approximately 10 ml of medication.

[0220] 3.2.5 After injection, record the start and end times of administration. It is recommended to complete the administration within approximately 5 minutes.

[0221] 4. Accompanying treatments during the process

[0222] The use of opioid drugs such as pethidine, fentanyl, sufentanil, alfentanil, remifentanil, and methadone is prohibited during the trial.

[0223] Acetaminophen is prohibited during the experiment. Aspirin is prohibited during the experiment.

[0224] The use of NSAIDs such as diclofenac sodium, parecoxib sodium, and ibuprofen is prohibited during the experiment.

[0225] The use of local anesthetics such as procaine, chloroprocaine, lidocaine, and bupivacaine is prohibited during the experiment.

[0226] The use of glucocorticoids such as dexamethasone and methylprednisolone is prohibited during the trial.

[0227] Carbamazepine, oxcarbazepine, sodium valproate, pregabalin, gabapentin, and other antiepileptic drugs are prohibited during the trial.

[0228] The use of anti-anxiety drugs such as chlordiazepoxide and diazepam is prohibited during the trial.

[0229] Antidepressants such as SSRIs, SNRIs, SARIs, NDRIs, TCAs, MAOIs, NASSA, and NRIs are prohibited during the trial.

[0230] Class III antiarrhythmic drugs are prohibited during the trial.

[0231] The use of potent CYP1A2 inhibitors, including ciprofloxacin and fluvoxamine, is prohibited during the trial.

[0232] The use of highly sensitive CYP1A2 substrates, including alosetron, caffeine, duloxetine, melatonin, rametamide, tasmetone, and tizanidine, is prohibited during the experiment.

[0233] During the trial, the use of potent CYP3A4 inhibitors such as ceritinib, clarithromycin, cobicistat, erticagvir in combination with ritonavir, ederaris, indinavir in combination with ritonavir, itraconazole, ketoconazole, lopinavir in combination with ritonavir, nefazodone, nelfinavir, paliravir in combination with ritonavir and (obitavir and / or daclatasvir), posaconazole, ritonavir, saquinavir in combination with ritonavir, telithromycin, telanavir in combination with ritonavir, and voriconazole is prohibited. The following CYP3A4 highly sensitive substrates are prohibited during the study: alfentanil, avanafil, budesonide, buspirone, conivatan, dafenapyr, darunavir, dasatinib, dronedarone, eletriptan, eplerenone, everolimus, felodipine, ibrutinib, indinavir, isaconazole, ivabradine, leboresen, lometapyr, lovastatin, lurasidone, maravirocin, midazolam, mobotinib, naloxetine, nisodipine, quetiapine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, ticagrelor, telanavir, tolvaptan, triazolam, vardenafil, and venetoclax.

[0234] The use of potent CYP3A4 inducers, including apalutamide, carbamazepine, enzalutamide, evanixib, rumacapto, mitotane, phenytoin, rifampin, and St. John's wort, is prohibited during the experiment.

[0235] The use of physical therapy methods that may have analgesic effects is prohibited during the trial.

[0236] Antiemetics such as 5-HT3, which may prolong the QTc interval, are prohibited during the trial.

[0237] The prophylactic use of antiemetics is prohibited during the trial.

[0238] Rescue analgesics are not intended for pain prevention, but only for postoperative rescue analgesia. They should be administered at any time after the initial dose of the study drug to maintain subject comfort. Morphine 2 mg (initial dose) is given intravenously as postoperative rescue analgesia, followed by slow bolus injections as needed (not exceeding 10 mg over 2 hours). Other analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), are not permitted for 72 hours after administration.

[0239] When a subject experiences nausea / vomiting or requests antiemetics, metoclopramide injection, aprepitant injection, or fosaprepitant meglumine for injection may be used. Antiemetics that prolong the QTc interval (such as ondansetron and domperidone) are prohibited. The use of antiemetics should follow the dosage instructions in the package insert, but they should not be used prophylactically (i.e., prophylactic use of antiemetics is prohibited when there are no signs / symptoms of nausea / vomiting or when the subject's needs are not taken into consideration).

[0240] 5. Test Results

[0241] 5.1 Efficacy Assessment

[0242] The efficacy assessment included using a numerical rating scale (NRS) to score the pain intensity at the surgical anal site and the time of first opioid administration postoperatively.

[0243] Among them, the NRS pain intensity score:

[0244] Resting and motor (cough) pain scoring time points: within 1 hour before surgery, and at 2, 4, 6, 8, 12, 18, and 24 hours after drug administration (time window ± 15 min), and at 36, 48, 60, and 72 hours (time window ± 1 hour). Resting pain scoring was completed before motor scoring. Subjects should be in a resting position (supine or supine) for at least 5 minutes before resting pain assessment.

[0245] Perform resting and exercise assessments before administering remedial analgesics.

[0246] Pain intensity was assessed after each dressing change or bowel movement. Resting and movement pain intensity were not assessed within 60 minutes of the change. Rescue analgesics were administered during dressing changes or bowel movements; pain intensity was assessed only during these movements (resting and movement scores were not required) before administering the rescue analgesics.

[0247] The time points for PK collection were: within 1 hour before surgery (blank sample), 15 minutes after drug administration (time window ±2 minutes), 1 hour, 4 hours, 8 hours, 12 hours, 24 hours (time window ±15 minutes), 48 hours, and 72 hours (time window ±1 hour).

[0248] The analgesia satisfaction rating was as follows: Before discharge, the subjects rated their analgesia satisfaction within 72 hours after administration using a five-point rating system (very satisfied = 4, satisfied = 3, average = 2, dissatisfied = 1, very dissatisfied = 0).

[0249] The area under the curve (AUC) of the primary efficacy endpoint, resting pain intensity score, over time. 0-72h Analysis of covariance (ANCOVA) was used to compare the differences in primary efficacy endpoints between the investigational drug and the control drug. The primary efficacy endpoints were analyzed using an ANCOVA model with treatment group as the main effect and baseline NRS values ​​as covariates. At a two-sided 5% significance level, the differences in primary efficacy endpoints between the investigational drug and the control drug were compared, and the AUC was calculated. 0-72h Least squares mean, standard deviation, standard error, and 95% CI of within-group and between-group differences.

[0250] For secondary efficacy endpoints, the area under the curve (AUC) for pain intensity scores was calculated using the Linear Trapezoidal Linear Interpolation method. For continuous variables, the same methods used in the master analysis as for the primary estimation target were employed based on their definitions. For binary variables, the proportion of participants within a group and the difference in proportions between groups achieving the relevant endpoint, along with their 95% CI, were calculated and analyzed using the chi-square test or Fisher's exact test, with p-values ​​reported. For ordinal data, the Wilcoxon rank-sum test was used for analysis, and p-values ​​were reported.

[0251] The results are shown in Table 2-4.

[0252] The time-resting pain intensity score superposition curve is shown in Figure 3. In Figure 3, the solid line represents group A of ropivacaine crystals, and the dashed line represents group A of ropivacaine hydrochloride injection.

[0253] Table 2: Area Under the Resting Pain Intensity Rating-Time Curve (AUC) 0-72h Comparative analysis of covariance Note 1. Analysis of variance (ANCOVA) was used to compare the area under the curve (AUC) of resting pain intensity score versus time between groups. 0- 72h The ANCOVA model will use the area under the curve (AUC) of the subjects' resting pain intensity scores from 0 to 72 hours. 0-72h 1. The dependent variable was ropivacaine crystal A 600mg group, with group number as the independent variable and baseline resting pain score as a covariate. 2. Intergroup comparison (ropivacaine crystal A 600mg group vs. ropivacaine hydrochloride injection group): the differences between groups were calculated.

[0254] The main analysis results showed that the area under the curve (AUC) of resting pain intensity score-time within 72 hours after administration was significantly higher in the ropivacaine crystal A 600mg group (N=11) and the ropivacaine hydrochloride injection group (N=12). 0-72h The mean values ​​were 83.2±16.02 and 192.3±15.33, respectively. The ropivacaine crystal A 600mg group was significantly superior to the ropivacaine hydrochloride injection group (P<0.0001).

[0255] For secondary efficacy endpoints, based on the m-ITT set, the analysis results of the area under the curve of resting pain intensity score-time at 0-24h, 0-48h, and 24-72h post-drug administration, and the area under the curve of exercise pain intensity score-time at 0-24h, 0-48h, 0-72h, and 24-72h post-drug administration, showed the same trend as the primary efficacy endpoints. The ropivacaine crystal A 600mg group had a significantly better postoperative analgesic effect than the ropivacaine hydrochloride injection group.

[0256] Table 3: Analysis of the area under the curve of pain intensity score-time, a secondary efficacy indicator Note: 1. Analysis of variance (ANCOVA) was used to compare the area under the curve of resting pain intensity score-time between groups. The ANCOVA model used the area under the curve (AUC) of the corresponding resting pain intensity score of the subjects as the dependent variable, the group as the independent variable, and the baseline resting pain score as a covariate; 2. Intergroup comparisons (CZ1S 600mg group vs. Ropivacaine Hydrochloride Injection group) were performed to calculate the differences between groups.

[0257] The area under the resting pain intensity score-time curve (AUC) within 0-24 hours after administration of ropivacaine crystal A 600mg group (N=11) and ropivacaine hydrochloride injection group (N=12) 0-24h The mean values ​​were 30.5±5.43 and 84.2±7.87, respectively. The ropivacaine crystal A 600mg group was significantly superior to the ropivacaine hydrochloride injection group (P<0.0001).

[0258] The area under the resting pain intensity score-time curve (AUC) within 0-48 hours after administration of ropivacaine crystal A 600mg group (N=11) and ropivacaine hydrochloride injection group (N=12) was compared between these two groups. 0-48h The mean values ​​were 62.6±9.66 and 150.2±14.09, respectively. The ropivacaine crystal A 600mg group was significantly superior to the ropivacaine hydrochloride injection group (P=0.0001).

[0259] The area under the resting pain intensity score-time curve (AUC) within 24-72 hours after administration of ropivacaine crystal A 600mg group (N=11) and ropivacaine hydrochloride injection group (N=12) 24-72h The mean values ​​were 51.8±7.16 and 109.0±12.79, respectively. The ropivacaine crystal A 600mg group was significantly superior to the ropivacaine hydrochloride injection group (P=0.0018).

[0260] Table 4: Comparison of rates of no use of rescue analgesics within 0-24h, 24h-72h and 0-72h after drug administration between groups Note: 1. The proportion of patients who did not use rescue analgesics was calculated using the Clopper-Pearson method with a 95% confidence interval; 2. The 95% confidence interval of the rate difference was estimated using the Newcombe method; Fisher's exact probability method was used to compare between groups (ropivacaine crystal A 600mg group vs. ropivacaine hydrochloride injection group) and calculate the differences between groups.

[0261] In the ropivacaine crystal A 600mg group (N=11), the proportion of subjects who had not used opioids 24 hours after administration was 81.8%, while in the ropivacaine injection group, the proportion of subjects who had not used opioids 24 hours after administration was 25.0%. The ropivacaine crystal A 600mg group was significantly superior to the ropivacaine hydrochloride injection group (P=0.0123).

[0262] In the ropivacaine crystal A 600mg group (N=11), the proportion of subjects who did not use opioids 72 hours after administration was 81.8%, while in the ropivacaine hydrochloride injection group, the proportion of subjects who did not use opioids 72 hours after administration was 25.0%. The ropivacaine crystal A 600mg group was significantly superior to the ropivacaine hydrochloride injection group (P=0.0123).

[0263] Results analysis: The proportion of subjects who did not use rescue analgesics was the same in both groups from 0-24 h and 0-72 h after administration, but significantly higher in the ropivacaine crystal A 600mg group than in the ropivacaine hydrochloride injection group (81.8% vs 25.0%; P = 0.0123). The proportion of subjects who did not use rescue analgesics was similar in both groups from 24-72 h after administration, with no statistically significant difference (90.9% vs 83.3%; P = 1.0000). This is likely because after surgery, as pain mediators and inflammatory mediators are absorbed and tissue damage is restored, the pain level gradually decreases. After 24 h of administration, the pain level had decreased to a tolerable range for the subjects.

[0264] Example 3: Pharmacokinetic Test

[0265] Collect blood samples for pharmacokinetic analysis (area under the curve, maximum concentration decrease, time to maximum plasma concentration, apparent terminal elimination half-life, apparent clearance, apparent volume of distribution, etc.).

[0266] Key PK data point conventions: a) PK parameters are calculated based on the actual sampling time. b) All blood drug concentrations below the lower limit of quantitation (BQL) are treated as "0" before Tmax and as missing after Tmax in PK analysis. However, for descriptive statistical analysis, they are treated as 0, and the number of BQLs at each time point is noted. Single-dose parameters are calculated based on the actual blood collection time using the Linear Trapezoidal Linear Interpolation method in the non-compartmental model (NCA module).

[0267] Blood drug concentration-time (CT) data analysis: Based on PKCS analysis, individual and mean CT curves and semi-logarithmic CT curves were plotted; the mean, standard deviation, median, maximum, minimum and coefficient of variation of drug concentrations at each time point were analyzed.

[0268] PK parameter analysis: Based on PKPS analysis, pharmacokinetic parameters for each subject were calculated using a non-compartmental model. The arithmetic mean, standard deviation, coefficient of variation, quartiles, maximum, minimum, geometric mean, and geometric coefficient of variation for each parameter were also calculated.

[0269] Between-group comparisons: Based on PKPS analysis, the PK parameters were transformed by the natural logarithm and then subjected to ANOVA, with the groups treated as fixed effects. The 90% confidence interval of the geometric mean ratio of the PK parameters (experimental drug / positive drug) was calculated.

[0270] The results are shown in Tables 5-7 and Figure 4.

[0271] Table 5: Summary of plasma concentrations in the ropivacaine hydrochloride group

[0272] Table 6: Summary of blood drug concentrations in the 600mg group of ropivacaine crystal injection A

[0273] Table 7: Summary of Pharmacokinetic Parameters

[0274] Pharmacokinetic analysis results showed that, based on the PKPS set, the Tmax pharmacokinetic parameters of ropivacaine in the ropivacaine crystal A 600mg group (N=11) and the ropivacaine hydrochloride injection group (N=12) were 7.88 (0.37, 12.2) h and 0.33 (0.28, 0.4) h, respectively. The Tmax of the ropivacaine crystal A 600mg group was... max The duration of action was significantly longer than that of the ropivacaine hydrochloride injection group (P = 0.0002). max The concentrations were 895.82±349.02 ng / mL and 615.83±211.06 ng / mL, respectively, with AUC... 0-t The concentrations were 23661.51±8048.99 h*ng / mL and 2522.72±1059.19 h*ng / mL, respectively, with AUC 0-∞ The concentrations were 23974.82±7976.08 h*ng / mL and 2598.42±1087.87 h*ng / mL, respectively. 1 / 2 The time to recovery (Tg) was 10.13 ± 2.98 h and 3.88 ± 2.53 h, respectively. Compared with the ropivacaine hydrochloride injection group, the Tg in the ropivacaine crystal A 600 mg group was... max Significantly increased, C max Within the safety window, it is indicated that ropivacaine crystal A 600mg, after local infiltration injection, provides a slow, non-constant release of ropivacaine, resulting in a stable and sustained blood concentration.

[0275] Example 4 Safety Test

[0276] This study evaluated the safety of ropivacaine crystal A for injection and ropivacaine hydrochloride. Safety endpoints included the occurrence of adverse events (AEs) and surgical events (SAEs) from the start of administration to 72 hours post-procedure.

[0277] Analysis was conducted using the Safety Dataset (SS). Adverse events recorded in this trial were coded according to MedDRA (V26.1 or later). The number and frequency of adverse events / reactions, adverse events / reactions during treatment, serious adverse events / reactions during treatment, and adverse events / reactions leading to dropout during treatment were summarized, and their incidence rates were calculated. The frequency, number, and percentage of the aforementioned AEs were summarized by treatment group according to the Systemic Organ Classification (SOC), Preferred Terminology (PT), and / or CTCAE classification.

[0278] This report summarizes and describes the laboratory test results (complete blood count, urinalysis, blood biochemistry, coagulation analysis, etc.) of each treatment group at each planned visit, and their changes relative to baseline. Changes in the clinical significance assessment results of laboratory tests relative to baseline for each treatment group at each planned visit are summarized in a crosstab format. All test results and abnormal results for complete blood count, urinalysis, blood biochemistry, coagulation analysis, etc., will be listed according to the subjects.

[0279] The changes in the overall clinical significance assessment results of electrocardiograms relative to baseline at each planned visit were summarized in the form of crosstabs for each treatment group; the diachronic analysis of measured values ​​before and after medication and changes from baseline; and a list of all electrocardiogram examination results and abnormal examination results of the subjects.

[0280] A cross-reference table of clinical assessments before and after medication and a detailed list of examination results.

[0281] No deaths occurred in this trial, and the subjects tolerated the injectable ropivacaine crystal A well.

[0282] The incidence of adverse events (AEs) in the ropivacaine crystal A 600mg group (N=11) and the ropivacaine hydrochloride injection group (N=12) were 4 (36.4%) vs 6 (50.0%), and the incidence of adverse reactions (ADRs) were 2 (18.2%) vs 2 (16.7%), respectively. No AEs of grade ≥3, SAEs, adverse events leading to shedding, or adverse events leading to death occurred. No unexpected adverse events occurred, and no systemic toxicity of local anesthetics occurred.

[0283] The incidence of adverse events (AEs) in the ropivacaine crystal A 600mg group (N=11) and the ropivacaine hydrochloride injection group (N=12) were 4 (36.4%) vs 6 (50.0%). According to PT classification: urinary retention 2 (18.2%) vs 4 (33.3%), fever 1 (9.1%) vs 1 (8.3%), nausea 1 (9.1%) vs 1 (8.3%), vomiting 0 vs 1 (8.3%), gastrointestinal pain 0 vs 1 (8.3%), hypoalbuminemia 0 vs 1 (8.3%), postoperative wound infection 0 vs 1 (8.3%), decreased lymphocyte count 0 vs 1 (8.3%), decreased platelet count 0 vs 1 (8.3%), incision site bleeding 1 (9.1%) vs 0, and anemia 0 vs 1. 1 (8.3%). Except for one case in the ropivacaine injection group, the postoperative wound infection outcome was improved / relieved, and the outcome of the other adverse events was recovered / cured.

[0284] The incidence of adverse drug reactions (ADRs) in the ropivacaine crystal A 600mg group (N=11) and the ropivacaine hydrochloride injection group (N=12) were 2 (18.2%) vs 2 (16.7%), respectively. According to PT classification: fever 1 (9.1%) vs 1 (8.3%), nausea 1 (9.1%) vs 1 (8.3%), vomiting 0 vs 1 (8.3%), gastrointestinal pain 0 vs 1 (8.3%), hypoalbuminemia 0 vs 1 (8.3%), decreased lymphocyte count 0 vs 1 (8.3%), decreased platelet count 0 vs 1 (8.3%), and anemia 0 vs 1 (8.3%).

[0285] In summary, the local infiltration of 600mg ropivacaine crystal A for injection provides good safety for postoperative analgesia after hemorrhoidectomy.

[0286] Although the embodiments have been described above, it will be apparent to those skilled in the art that modifications can be made without departing from the invention. Such modifications are considered possible variations that are included within the scope of the invention.

Claims

1. A method for preventing or treating postoperative pain, comprising administering to an individual in need a pharmaceutical composition containing ropivacaine crystal A.

2. The method according to claim 1, wherein the aspect ratio of the ropivacaine crystal A is approximately 1:(1-2).

3. The method of claim 1 or 2, wherein at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystal A has an aspect ratio of about 1:(1 to 2).

4. The method as described in any of the preceding claims, wherein the ropivacaine crystal A has a D 50 It is approximately 5-10 μm.

5. The method as described in any of the preceding claims, wherein the crystal size distribution width (SPAN) value of the ropivacaine crystal A is approximately 1 to 2.

6. [According to Rule 91, Corrected 17.09.2026] The method of any of the preceding claims, wherein the ropivacaine crystal A has the particle morphology shown in FIG2.

7. The method of any of the preceding claims, wherein the ropivacaine crystal A has the XRPD diffraction pattern shown in FIG1.

8. The method as claimed in any of the preceding claims, wherein postoperative pain includes postoperative pain following hemorrhoid surgery.

9. The method of any of the preceding claims, wherein postoperative pain includes traumatic pain, chemical pain, neuropathic pain, and inflammatory pain.

10. The method as claimed in any of the preceding claims, wherein postoperative pain includes acute pain and / or chronic pain.

11. The method of any of the preceding claims, wherein treatment or prevention includes reducing, inhibiting, reversing, slowing or stopping the progression or severity of an existing condition, disease, symptom or illness.

12. The method of any of the preceding claims, wherein treatment or prevention includes curing, alleviating, reducing or eliminating the course or severity of a disease, condition, symptom or illness.

13. The method of any of the preceding claims, wherein ropivacaine crystal A is administered to the individual in need by injection.

14. The method of any of the preceding claims, comprising administering ropivacaine crystal A by means of perianal injection to an individual in need.

15. The method as claimed in any of the preceding claims, comprising: Select an entry point for the injection needle at the desired individual's body site, insert the needle into the patient's body at the entry point, and administer ropivacaine crystal A locally to the desired individual's body through the injection needle.

16. The method of claim 15, wherein the body part is around the anus.

17. The method as described in any one of claims 15 to 16, wherein the body part is located 0.5-3 cm from the anal margin.

18. The method of any one of claims 15 to 17, wherein the body part is the peripheral nerve of the anal end.

19. The method of any one of claims 15 to 18, comprising: Choose the injection point around the anus for the individual in need; The injection needle is selected at least 4 entry points; The injection needle is inserted into the individual in need at the selected point; The pharmaceutical composition is injected locally into the perianal area of ​​the individual in need via an injection needle; the pharmaceutical composition comprises ropivacaine crystals A.

20. The method of claim 19, wherein the injection needle is selected from 4 to 8 points, preferably 4, 5, 6, 7 or 8 points.

21. The method as described in claim 19 or 20, wherein the four points are the cutting points at 3, 6, 9 and 12 o'clock.

22. The method of any of the preceding claims, wherein the pharmaceutical composition is injected into the perianal anal sphincter and subcutaneous tissue.

23. The method of any of the preceding claims, wherein the amount of the pharmaceutical composition injected at one time is less than 6 mL, preferably 5 mL, 4 mL, 3 mL, or 2 mL.

24. The method of any of the preceding claims, wherein the total amount of the pharmaceutical composition used is less than 30 mL.

25. The method according to any of the preceding claims, wherein the dose of ropivacaine crystal A in the pharmaceutical composition is 200 mg-800 mg, preferably 200 mg-750 mg, 200 mg-700 mg, 200 mg-650 mg, 200 mg-600 mg, 200 mg-550 mg, 200 mg-500 mg, 200 mg-450 mg, 200 mg-400 mg, 200 mg-350 mg, 200 mg-300 mg, 200 mg-250 mg, 350 mg-650 mg, 400 mg-600 mg, 450 mg-550 mg, or 500 mg-600 mg.

26. The method of any of the preceding claims, wherein the pharmaceutical composition is a dosage form suitable for injection.

27. The method of any of the preceding claims, wherein ropivacaine crystal A may be used in combination with other anesthetics or other analgesics or in an anesthesia or analgesia regimen with other anesthetics or other analgesics.

28. The method of claim 27, wherein the other anesthetic agent comprises a general anesthetic agent and a local anesthetic agent, wherein the general anesthetic agent comprises etomidate, ketamine, ciprofol, propofol, and thiopental sodium, and the local anesthetic agent is selected from benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, propoxycaine, procaine, amethocaine, articaine, bupivacaine, eticaine, levobupivacaine, lidocaine, mepivacaine, and trimecaine; And / or, the anesthetic adjuvant drugs include midazolam and diazepam; And / or, the other analgesics include opioid analgesics, antipyretic analgesics and anti-inflammatory drugs, and adjunctive analgesics; Preferably, the opioid analgesic is selected from hydrocodone, dextropropoxyphene, codeine, dihydrocodeine, tramadol, morphine, oxycodone, hydromorphone, fentanyl, sufentanil, remifentanil, buprenorphine, pethidine, nalbuphine, methadone, levorphanol, pentazocine, or naloxone. Preferably, the antipyretic analgesic is selected from: acetaminophen, NSAIDs (preferably selective COX-2 inhibitors (e.g., celecoxib) or non-selective inhibitors (e.g., ibuprofen, aspirin, diclofenac, naproxen)); Preferably, the adjunctive analgesic is selected from: anticonvulsants (e.g., gabapentin), tricyclic antidepressants (e.g., amitriptyline), psychotropic drugs, NMDA receptor antagonists (e.g., ketamine), α2-adrenergic receptor agonists (e.g., dexmedetomidine), and glucocorticoids (e.g., dexamethasone).

29. The method of any one of claims 1 to 26, wherein ropivacaine crystal A is not used in combination with other anesthetics or analgesics.

30. Use of ropivacaine crystal A in the preparation of pharmaceutical compositions for the prevention or treatment of postoperative pain.

31. The use as described in claim 30, wherein, The aspect ratio of ropivacaine crystal A is approximately 1:(1-2).

32. The use as described in claim 30 or 31, wherein at least about 80%, at least about 85%, at least about 90%, and at least about 95% of the ropivacaine crystal A has an aspect ratio of about 1:(1 to 2).

33. The use as described in any one of claims 30 to 32, wherein the ropivacaine crystal A has a D 50 It is approximately 5-10 μm.

34. The use as described in any one of claims 30 to 33, wherein the crystal size distribution width (SPAN) value of the ropivacaine crystal A is about 1 to 2.

35. The use as described in any one of claims 30 to 34, wherein the ropivacaine crystal A has the XRPD diffraction pattern shown in FIG1.

36. The use as described in any one of claims 30 to 35, wherein the pharmaceutical composition is a dosage form suitable for injection.

37. The use as described in any one of claims 30 to 36, wherein postoperative pain includes postoperative pain from hemorrhoid treatment.

38. The use as described in any one of claims 30 to 37, wherein postoperative pain includes traumatic pain, chemical pain, neuropathic pain, and inflammatory pain.

39. The use as described in any one of claims 30 to 38, wherein postoperative pain includes acute pain and / or chronic pain.

40. The use as described in any one of claims 30 to 39, wherein the treatment or prevention includes reducing, inhibiting, reversing, slowing down, or stopping the progression or severity of an existing condition, disease, symptom, or illness.

41. The use as described in any one of claims 30 to 40, wherein treatment or prevention includes cure, relief, reduction or elimination of the course or severity of a disease, condition, symptom or illness.

42. The use as described in any one of claims 30 to 41, wherein the dose of ropivacaine crystal A is 200 mg to 800 mg, preferably 200 mg to 750 mg, 200 mg to 700 mg, 200 mg to 650 mg, 200 mg to 600 mg, 200 mg to 550 mg, 200 mg to 500 mg, 200 mg to 450 mg, 200 mg to 400 mg, 200 mg to 350 mg, 200 mg to 300 mg, 200 mg to 250 mg, 350 mg to 650 mg, 400 mg to 600 mg, 450 mg to 550 mg, or 500 mg to 600 mg.

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