Amorphous substance of pentazocine pamoate and pharmaceutical composition thereof

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to an amorphous form of pentazocine dihydroxynaphthyl acid and its pharmaceutical composition. The amorphous form of pentazocine dihydroxynaphthyl acid of this invention exhibits low solubility in water and other media. This low solubility can improve the stability and sustained-release effect of pentazocine dihydroxynaphthyl acid, effectively prolonging the duration of action, and can be used to prepare pain medications.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to an amorphous form of pentazocine dihydroxynaphthyl acid and its pharmaceutical composition. Background Technology

[0002] Postoperative pain is usually caused by tissue trauma (incisions, traction, suturing, etc. during surgery), and is an acute pain that occurs immediately after surgery (Treasure Island (FL): StatPearls Publishing, 2022). It continues to occur during the tissue damage and repair process, seriously affecting the patient's physical recovery and mental health. The mechanism of postoperative pain (Research Progress on the Mechanism and Treatment of Postoperative Pain, 2020, 49: 1-5) is a complex process of multiple central and peripheral sensitizations. Surgical trauma directly damages nerve endings in the affected area, leading to an inflammatory response, which releases pain-inducing substances such as serotonin and inflammatory factors; it can also exacerbate the activity of neurons in the dorsal horn of the spinal cord, thereby aggravating the pain. Postoperative pain has a high incidence rate and usually lasts for several days. If it is not adequately controlled in the initial state, it may continue to develop into chronic pain. Therefore, long-acting analgesia meets the clinical needs of postoperative pain treatment.

[0003] Long-acting injectable drugs are now widely used in the treatment of diseases (Guangdong Pharmaceutical University Journal, 2015;31(5):584, West China Pharmaceutical Journal, 2016;31(3):324-326). In the 1990s, the FDA approved the first atypical antipsychotic long-acting injectable drug, risperidone (RISP) polymeric microspheres. Subsequently, long-acting injectable formulations of drugs such as fluphenazine (FLP), haloperidol (HAL), olanzapine (OLZ), aripiprazole (APZ), and paliperidone (PALI) were also approved for marketing. Existing long-acting injectable technologies mainly include prodrugs, microspheres, microcapsules, injectable implants, gels, in-situ storage, and poorly soluble salts (Int J Pharm, 2016;499(1-2):358-367).

[0004] Salt formation technology is generally used to improve the solubility of insoluble compounds (Adv Drug Deliv Rev, 2007;59(7):603-616). In contrast, sparingly soluble salt technology converts water-soluble drugs into sparingly soluble salts to control drug release and prolong the duration of drug action (Chinese Journal of New Drugs, 2013;22(05):547-555). As a simple approach in sustained-release formulations, sparingly soluble salt technology has opened up a broader research space for the development of sustained-release formulations. Currently marketed long-acting injectables using sparingly soluble salt technology, such as olanzapine monohydrate dihydroxynaphthyl salt injection, have reduced the dosing frequency from once daily to once every 2 or 4 weeks, and extended the plasma half-life from 30 hours to nearly 30 days (Int J Clin Pract, 2009;63(1):140-150). Although olanzapine dihydroxynaphthyl salt injection demonstrates good bioavailability, biocompatibility, and therapeutic efficacy, some adverse events still occur during injection. During intramuscular injection, the pH at the injection site is similar to that of a laboratory buffered saline solution with a pH of 7.4–7.6. Post-injection delirium / sedation syndrome (PDSS) has still occurred in patients receiving olanzapine dihydroxynaphthyl salt. The main causes of these adverse events are believed to be direct injection into a vein or puncture of a blood vessel leading to blood leakage into the injection site, and the high solubility of olanzapine dihydroxynaphthyl salt and other drugs in proteins and lipids.

[0005] Compared to other sustained-release technologies, this technology is only suitable for drugs that can form salts, and the types of salts formed are limited. Because these injectables lack targeting, the increased residence time prolongs the drug's half-life and also increases the risk of adverse reactions. Furthermore, the release rate of the drug after salt formation is uncontrollable, lacking flexibility in administration, and is not suitable for drugs with high toxicity, either inherently or through degradation products.

[0006] Pentazocine, chemically known as (2) R 6 R , 11 R )-cis-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methylene-3-benzo[a]octane-8-ol, with the following structural formula:

[0007] ;

[0008] Its hydrochloride and lactate salts are clinically known for their use in treating various types of pain, such as cancer pain, traumatic pain, and postoperative pain. They can also be administered preoperatively or before anesthesia as an adjunct to surgical anesthesia. The molecular formula of the base is: C 19 H 27 NO, molecular weight: 285.43. pKa1=8.0 (tertiary amine), pKa2=9.7 (phenolic hydroxyl group), melting point: 150-158℃.

[0009] Long-acting salts of amine-containing pharmaceutical active ingredients, such as dihydroxynaphthyl salts and the sinet family, have received relatively little attention and have had limited commercial success. Currently, only one sinet, salmeterol sinet, is listed in the FDA's Orange Book of Drugs and has been approved for marketing. Similarly, only four dihydroxynaphthyl salts have been approved for marketing: hydroxyzine dihydroxynaphthyl salt, imipramine dihydroxynaphthyl salt, olanzapine dihydroxynaphthyl salt, and triptorelin dihydroxynaphthyl salt.

[0010] Pamoic acid, with the following structural formula:

[0011] ;

[0012] The molecular formula is: C 23 H 16 O6, molecular weight: 388.38, pKa1=2.51 (tertiary amine), pKa2=3.1 (phenolic hydroxyl group), melting point approximately 280℃ (decomposes).

[0013] Existing technology patent documents:

[0014] JPS5379870A and WO2010016219A1: disclose pentazocine and its acid salt;

[0015] CN113831251A and CN113845429A: A memantine bis(hydroxynaphthalate) crystal, its preparation method and application;

[0016] CN113423686A: Ketamine dihydroxynaphthyl salt and its uses; Ketamine dihydroxynaphthyl salt and its uses;

[0017] CN112752752A: A method for preparing escitalopram bis(hydroxynaphthyl) salt crystal form A;

[0018] CN111233878A: A galantamine dihydroxynaphthyl salt and its preparation method;

[0019] CN111212640A: Dihydroxynaphthyl salt of monoamine anti-Parkinson's drugs, its preparation method and its uses;

[0020] CN106831594A: Clonidine dihydroxynaphthyl salt and its preparation method;

[0021] CN109311832A: Permocyanate of vortioxetine and its crystal forms;

[0022] WO2018177232A1: Poorly soluble complexes or solvates thereof, pharmaceutical compositions and their use.

[0023] Selection of active pharmaceutical ingredient (API) salts:

[0024] Different salts of an API can possess different properties. Such variations in the properties of different salts can provide a basis for improving formulations, for example, by promoting better processing or handling characteristics, improving dissolution profiles, or improving stability and shelf life. These variations in the properties of different salts can also provide improvements to the final dosage form, for example, if they contribute to improved bioavailability. Different salts of APIs can also produce various polymorphs, which in turn can provide further opportunities for providing improved active pharmaceutical ingredients and finished products.

[0025] Polymorphism, the appearance of different crystal forms, is a characteristic of some molecules and molecular complexes. A single compound such as pentazocine can produce various polymorphs with different crystal structures and physical properties, such as melting point, thermal behavior (e.g., measured by thermogravimetric analysis – "TGA" or differential scanning calorimetry – "DSC"), X-ray powder diffraction (XRPD) patterns, infrared absorption fingerprints, Raman absorption fingerprints, and solid-state properties. 13 C-NMR spectroscopy. One or more of these techniques can be used to distinguish different polymorphic forms of compounds.

[0026] Novel salts and solid forms of active pharmaceutical ingredients (APIs), as well as solvates, can offer advantageous properties such as ease of handling, ease of processing, storage stability, and ease of purification, or serve as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. Novel polymorphic forms and solvates of pharmaceutically useful compounds can also provide opportunities to improve the performance characteristics of drug products (dissolution profiles, bioavailability, etc.). For example, by providing products with different properties (e.g., different crystal habits, higher crystallinity, or polymorphic stability), they can offer better processing or handling characteristics, improved dissolution, or improved shelf life, expanding the pool of materials available to formulation scientists for formulation optimization. For at least these reasons, there is a need for additional pentazocine salts and solid forms.

[0027] It is well known that the pH value of muscle tissue changes with exercise, stress, and injury, which can affect drug solubility and thus the absorption rate of injected drugs. Therefore, it is ideal to find an injectable sustained-release formulation in which the release rate of the active ingredient is least dependent on pH.

[0028] Currently, common knowledge generally teaches that selecting a salt with the desired combination of properties remains a difficult semi-empirical choice, requiring a trade-off between the properties of the salt form. However, it is still difficult to assess which salt form is best suited for screening a particular drug candidate.

[0029] Screening for drug salts is a challenging semi-empirical process, as drug hygroscopicity significantly impacts flowability and even stability. Drug solubility is crucial for formulation preparation, dissolution, and absorption. However, achieving optimal drug solubility without compromising hygroscopicity, while obtaining candidate drug salts with suitable stability, solubility, and hygroscopicity, remains a difficult task.

[0030] In addition, pentazocine has shown promising therapeutic effects in the clinical treatment of pain relief for various surgical anesthesias, including anesthesia induction, intraoperative anesthesia, and postoperative analgesia; postoperative analgesia in various surgical departments; analgesia for various laparoscopic surgeries; analgesia for painless abortions; and analgesia and related behavioral symptoms in cancer patients. However, its potential has been limited by side effects such as short-acting and frequent use, including salivation, nausea, dizziness, respiratory depression, and physical dependence. Furthermore, its metabolism in the human body is complex and unpredictable, which has posed difficulties for the development of pentazocine.

[0031] Therefore, there is a need to further explore new pentazocine salts and their polymorphs that have good efficacy, few side effects, better pharmacokinetic properties, are suitable for drug development, and have suitable and reliable formulation and preparation characteristics. Summary of the Invention

[0032] Pentazocine tablets (TALWIN) dissolve slowly or not completely after oral administration. Furthermore, due to first-pass metabolism, their bioavailability is low, only about 18%–22%. They are also extensively metabolized, and large-scale post-marketing surveillance studies have shown significant gastrointestinal side effects. While intravenous pentazocine injection (TALWIN) has high bioavailability, its short elimination half-life and short average residence time lead to increased dosing frequency, reduced patient compliance, and lower bioavailability, limiting its clinical application. Additionally, immediate-release injections have a short duration of action, mostly lasting only 3–4 hours, resulting in short postoperative pain relief. Therefore, designing and developing suitable pentazocine formulations to prolong the duration of action is necessary to meet clinical needs.

[0033] Pentazocine has a short duration of action, forcing patients to take it frequently. Furthermore, like other opioids, pentazocine is considered to have the potential for abuse. To address this issue, pentazocine nalonolone tablets are marketed in the US and Japan for oral administration, three times daily. Therefore, an alternative formulation is needed that provides a prolonged release of pentazocine, thereby reducing the frequency of dosing. Additionally, an alternative formulation is needed to overcome the problems associated with oral administration and reduce the opportunity for abuse, so that the release of the analgesic is not restricted by the patient or other external sources.

[0034] The inventors of this invention have developed a novel dosage form for parenteral administration that provides prolonged release of pentazocine. Because pentazocine has a short duration of analgesia (maximum 6 hours), prolonged drug action will significantly benefit patients by maintaining a sustained level of pain relief. The prolonged release of pentazocine also overcomes the problem of insufficient pain relief caused by fluctuations in dosing frequency during oral treatment. This invention is achieved using the following technical solutions:

[0035] The purpose of this invention is to overcome the shortcomings of the prior art and provide a pentazocine dihydroxynaphthyl acid having the structure shown in formula (I):

[0036] ;

[0037] The pentazocine dihydroxynaphthyl acid provided by this invention is an amorphous powder. Its X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown below. Figure 1 As shown.

[0038] This invention also provides a method for preparing pentazocine dihydroxynaphthyl acid, which involves reacting pentazocine with dihydroxynaphthyl acid in an organic solvent to form a salt, as shown in the following reaction formula:

[0039] ;

[0040] The organic solvents referred to are one or more of the following: methanol, ethanol, isopropanol, n-butanol, acetone, butanone, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, diethyl ether, isopropyl ether, petroleum ether, n-hexane, tetrahydrofuran, dioxane, methyltetrahydrofuran, and DMSO. During the solvent screening process, many cases where salt formation is not possible are described in the comparative examples below.

[0041] Another object of the present invention is to provide an injectable composition comprising pentazocine dihydroxynaphthyl acid, wherein the composition provides extended release of pentazocine for at least 48 hours. An embodiment of the present invention provides an injectable composition comprising pentazocine dihydroxynaphthyl acid, wherein the composition provides extended release of pentazocine for up to one month, preferably up to 15 days, more preferably up to 7 days, and most preferably up to 5 days.

[0042] The injectable compositions of the present invention can be formulated into liquid compositions of pentazocine dihydroxynaphthyl acid for parenteral administration, providing prolonged release. Pentazocine dihydroxynaphthyl acid can be suspended and / or dispersed in an aqueous or non-aqueous carrier. The compositions further include one or more pharmaceutically acceptable excipients.

[0043] The injectable composition of pentazocine dihydroxynaphthyl acid according to the present invention forms a homogeneous solution or an aqueous / non-aqueous suspension / dispersion when formulated as a liquid composition. Preferably, pentazocine dihydroxynaphthyl acid forms an aqueous suspension. Optionally, the liquid composition according to the present invention is lyophilized and can be reconstituted for injection prior to administration.

[0044] Preferably, the liquid formulation comprises pentazocine dihydroxynaphthyl acid. The particle size (D90) of the liquid composition or lyophilized powder of pentazocine dihydroxynaphthyl acid according to the invention is less than 50 micrometers, preferably less than 30 micrometers, more preferably less than 15 micrometers, and most preferably less than 10 micrometers. Surprisingly, when formulated according to the invention, the particle size of pentazocine dihydroxynaphthyl acid was observed to interfere with drug release. Therefore, particle size optimization is crucial for the expected drug release. Preferably, the particle size (D90) of the suspended or dispersed particles of pentazocine dihydroxynaphthyl acid in the liquid composition is less than 50 micrometers, more preferably less than 15 micrometers. Furthermore, after reconstitution of the lyophilized powder with the desired carrier, the particle size (D90) of the suspended or dispersed particles of pentazocine dihydroxynaphthyl acid in the liquid composition is less than 50 micrometers, more preferably less than 15 micrometers.

[0045] The pH value of the liquid composition prepared according to the present invention is in the range of 4 to 9, preferably 5.5 to 8.5.

[0046] Pentazocine dihydroxynaphthyl acid injectable aqueous suspension can be used as a ready-to-use suspension or lyophilized powder to improve the physical and chemical stability of the formulation.

[0047] Lyophilized powders can be prepared by methods known in the art. Alternatively, cryoprotectants, such as cryoprotectants, can be used during the lyophilization process. Cryoprotectants are agents that protect the formulation composition from the harmful effects of freezing. For injectable suspensions, cryoprotectants prevent clumping caused by the lyophilization process. The type and amount of cryoprotectant used as a diluent for the composition are crucial for determining the injectability and injectability of the composition after lyophilization. Furthermore, the lyophilization process and duration are crucial for providing the desired filter cake or liquid suspension powder. Examples of cryoprotectants that can be used include, but are not limited to, mannitol, lactose, sucrose, trehalose, sorbitol, glucose, etc. Mannitol and lactose are preferred cryoprotectants.

[0048] The injectable composition of the present invention comprises a suitable aqueous carrier, which is water for injection, optionally including a suspending agent or viscosity modifier and a wetting agent, and optionally one or more of a preservative, a pH adjuster, a buffer, an isotonic maintainer or osmotic maintainer and a release rate retarder.

[0049] In some embodiments of the present invention, the non-aqueous carrier comprising the composition includes, but is not limited to, cottonseed oil, dibutyl phthalate, diethyl phthalate, dimethyl ethyl ether, dimethyl phthalate, dimethyl sulfoxide, ethyl acetate, ethyl lactate, ethyl oleate, glycerol, saccharifuranol, isopropyl myristate, isopropyl palmitate, light mineral oil, medium-chain triglycerides (MCT), methyl lactate, mineral oil, monoethanolamine, octyldodecyl alcohol, olive oil, peanut oil, polyethylene glycol, castor oil, propylene carbonate, propylene glycol, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, triacetin, tricaprylic acid, triethyl glycerol, triethanolamine, triethyl citrate, triolein, alcohol, almond oil, benzyl alcohol, benzyl benzoate, butylene glycol, carbon dioxide, or mixtures thereof. Alternatively, pharmaceutically acceptable excipients, such as thickeners, preservatives, antioxidants, and any combination thereof, may be added to the non-aqueous carrier.

[0050] Thickeners are used in some embodiments of the present invention, including but not limited to aluminum monostearate, ethyl cellulose, triglycerides, hydrogenated castor oil, and mixtures thereof.

[0051] The injectable compositions according to the invention further include one or more pharmaceutically acceptable ingredients selected from, but not limited to, buffers, wetting agents, viscosity modifiers, sustained-release rate agents, isotonic agents, preservatives, stabilizers, pH adjusters, plasticizers, and mixtures thereof.

[0052] In some embodiments of the present invention, wetting agents are used, including but not limited to lecithin, polyoxyethylene and polyoxypropylene ethers, sodium deoxycholate, benzalkonium chloride, benzyl chloride, hexadecylpyridine chloride, sodium docusate, glycine, phospholipids, poloprazole, polyoxyethylene alkyl ethers, polyoxyethylene monolauryl ethers, alkylphenyl polyoxyethylene ethers, polyoxyethylene-polyoxypropylene copolymers (poloxam), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20)), polyoxyethylene stearate, sodium dodecyl sulfate, sorbitan esters, trioctyl glycosides, and mixtures thereof.

[0053] In some embodiments of the present invention, sustained-release rate agents are used, including but not limited to modified dextran, sucrose isobutyrate acetate, medium-chain triglycerides, glucose, polymer solutions (prepared by mixing polymers in a suitable solvent), and mixtures thereof.

[0054] The stabilizers used in some embodiments of the present invention include, but are not limited to, mannitol, sorbitol, sucrose, glycine, lactose, amino acids, sugars, α-tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, fumaric acid, malic acid, monothioglycerol, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, sodium sulfite, tartaric acid, vitamin E, and mixtures thereof.

[0055] In some embodiments of the present invention, pH adjusters are used, including but not limited to sodium hydroxide, hydrochloric acid, or mixtures thereof.

[0056] Plasticizers, including but not limited to polyethylene glycol, stearic acid, palmitic acid, cholesterol, hexadecyl palmitate, poloxamer, and mixtures thereof, are used in some embodiments of the present invention.

[0057] The preservatives used in this invention are selected to maintain the amount of the composition. Suitable preservatives used in some embodiments of this invention include, but are not limited to, benzalkonium chloride, methyl, ethyl, propyl or p-hydroxybenzoate, benzyl alcohol, phenethyl alcohol, phenethyl alcohol, benzylthionine, trichlorobutanol, potassium sorbate, or combinations thereof.

[0058] In some embodiments of the invention, buffers are used, including but not limited to citrates, acetates, or phosphates or mixtures thereof.

[0059] In some embodiments of the present invention, isotonic agents are used, including but not limited to sodium chloride, potassium chloride, sugars and sugar alcohols including but not limited to glucose, sucrose, trehalose or glycerol, and any component alone or in combination from the amino acid, sugar, and salt groups.

[0060] The viscosity modifiers used in this invention are known to those skilled in the art, including but not limited to gum arabic, agar, alginate, bentonite, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, carrageenan, colloidal silica, ethyl cellulose, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hydroxypropyl starch, hydroxypropyl cellulose, methyl cellulose, myristyl polyethylene glycol, polyvinyl phthalate, polyvinyl alcohol, potassium chloride, povidone starch, stearyl alcohol, sucrose, or mixtures thereof.

[0061] The lipids used according to the present invention are of synthetic or semi-synthetic origin. Examples of lipids known to those skilled in the art include, but are not limited to, phosphatidylcholine, myristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, dipeptidoyl phosphatidylcholine, phosphatidylglycerol, cholesterol, and mixtures thereof. In some embodiments of the present invention, the composition comprises solid lipids including tristearate, trifolin, tripalmitate, dihydroxyhexylglycerol, lauryl acid, cholesterol, stearic acid, palmitic acid, and mixtures thereof.

[0062] Nonionic surfactants are used in some embodiments of the present invention, including but not limited to acetyl alcohol, cocamidodiethanolamine, cocamidomonoethanolamine, poloxamer, polyglycerol, polysorbate, hummus, Tween and mixtures thereof.

[0063] However, the present invention will be further illustrated by the following embodiments, but its scope is not limited to these embodiments. Attached Figure Description

[0064] Figure 1 X-ray diffraction pattern of pentazocine dihydroxynaphthyl acid.

[0065] Figure 2 The structural formula is pentazocine dihydroxynaphthyl acid.

[0066] Figure 3 The 1H NMR spectrum is for pentazocine dihydroxynaphthyl acid.

[0067] Figure 4 This is the carbon spectrum of pentazocine dihydroxynaphthyl acid.

[0068] Figure 5 The TGA is pentazocine dihydroxynaphthyl acid.

[0069] Figure 6 DSC for pentazocine dihydroxynaphthyl acid.

[0070] Figure 7 The IR of pentazocine dihydroxynaphthyl acid.

[0071] Figure 8 XRD pattern of pentazocine dihydroxynaphthyl acid crystals.

[0072] Figure 9 Comparison of pK curves for rat dihydroxynaphthyl pentazocine aqueous suspension and pentazocine alkaloid suspension.

[0073] Figure 10 The pK curves for comparing pentazocine lyophilized powder in beagle dogs are shown. Detailed Implementation

[0074] The following embodiments can further describe the present invention; however, these embodiments should not be construed as limiting the scope of the present invention.

[0075] Example 1: Preparation of pentazocine dihydroxynaphthyl acid

[0076] 0.68 g of dihydroxynaphthyl acid and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask and heated to 55–60 °C. 1.0 g of pentazocine was slowly added and dissolved. The mixture was kept warm and stirred for 30 min. After stirring, the mixture was concentrated to dryness, and 10 ml of methanol was added. The mixture was heated to reflux and dissolved. The temperature was slowly lowered to 0–5 °C, and a viscous oily substance precipitated, which gradually hardened into an amorphous block.

[0077] Example 2: Preparation of pentazocine dihydroxynaphthyl acid

[0078] 0.68 g of dihydroxynaphthyl acid and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask and heated to 55–60 °C. 1.0 g of pentazocine was slowly added until dissolved, and the mixture was stirred at this temperature for 30 min. After stirring, the mixture was concentrated to dryness, and 40 ml of isopropanol was added. The mixture was heated to reflux until dissolved, and then slowly cooled to 20–25 °C, precipitating a granular solid. The solid was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.12 g of a yellow amorphous solid, with a yield of 66.66%.

[0079] Example 3: Preparation of pentazocine dihydroxynaphthyl acid

[0080] 0.68 g of dihydroxynaphthyl acid and 40 ml of isopropanol were added to a 50 ml reaction flask and heated to reflux. 1.0 g of pentazocine was slowly added and dissolved. The mixture was kept warm and stirred for 30 min. After stirring, the temperature was slowly lowered to 20–25 °C, and granular solid precipitated. The mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.21 g of yellow amorphous solid, with a yield of 72.02%.

[0081] Example 4: Preparation of pentazocine dihydroxynaphthyl acid

[0082] 6.8 g of dihydroxynaphthyl acid and 400 ml of isopropanol were added to a 500 ml reaction flask and heated to reflux. 10 g of pentazocine was slowly added and dissolved. The mixture was kept warm and stirred for 30 min. After stirring, the temperature was slowly lowered to 20–25 °C, and granular solid precipitated. The mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 13.1 g of yellow amorphous solid, with a yield of 77.97%.

[0083] Example 5: Preparation of pentazocine dihydroxynaphthyl acid

[0084] 68g of dihydroxynaphthyl acid and 4000ml of isopropanol were added to a 5000ml reaction flask and heated to reflux. 100g of pentazocine was slowly added and dissolved. The mixture was kept warm and stirred for 30 minutes. After stirring, the temperature was slowly lowered to 20-25℃, and granular solid precipitated. The mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 119g of a yellow amorphous solid, with a yield of 70.83%.

[0085] Example 6: Preparation of pentazocine dihydroxynaphthyl acid

[0086] 0.68 g of dihydroxynaphthyl acid and 40 ml of isopropanol were added to a 50 ml reaction flask and heated to reflux. 1.0 g of pentazocine was slowly added and dissolved. The mixture was kept warm and stirred for 30 min. After stirring, the temperature was slowly lowered to 0–5 °C, and granular solid precipitated. The mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.39 g of yellow amorphous solid, with a yield of 82.64%.

[0087] Example 7: Preparation of pentazocine dihydroxynaphthyl acid

[0088] 0.68 g of dihydroxynaphthyl acid and 50 ml of isopropanol were added to a 50 ml reaction flask and heated to reflux. 1.0 g of pentazocine was slowly added and dissolved. The mixture was kept warm and stirred for 30 min. After stirring, the temperature was slowly lowered to 0–5 °C, and granular solid precipitated. The mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.19 g of yellow amorphous solid, with a yield of 70.83%.

[0089] Example 8: Preparation of pentazocine dihydroxynaphthyl acid

[0090] 0.68 g of dihydroxynaphthyl acid and 60 ml of isopropanol were added to a 50 ml reaction flask and heated to reflux. 1.0 g of pentazocine was slowly added and dissolved. The mixture was kept warm and stirred for 30 min. After stirring, the temperature was slowly lowered to 0–5 °C, and granular solid precipitated. The mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.23 g of yellow amorphous solid, with a yield of 73.21%.

[0091] Example 9: Preparation of pentazocine dihydroxynaphthyl acid

[0092] 1.36 g of dihydroxynaphthyl acid and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask and heated to 55–60 °C. 1.0 g of pentazocine was slowly added, and the mixture was stirred at this temperature for 30 min. The mixture was then filtered to remove insoluble matter. The solution was concentrated to dryness, and 40 ml of isopropanol was added. The mixture was heated to reflux until dissolved, and then slowly cooled to 20–25 °C, precipitating a granular solid. The solid was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.02 g of a yellow amorphous solid, with a yield of 60.71%.

[0093] Example 10: Preparation of pentazocine dihydroxynaphthyl acid

[0094] 1.36 g of dihydroxynaphthyl acid, 1.0 g of pentazocine, and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask. The mixture was heated to 65–70 °C and stirred for 30 min. The insoluble matter was removed by filtration. The mixture was concentrated to dryness, and 40 ml of isopropanol was added. The mixture was heated to reflux and dissolved. The temperature was slowly lowered to 20–25 °C, and granular solid precipitated. The mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to give 1.12 g of a yellow amorphous solid, with a yield of 66.66%.

[0095] Example 11: Preparation of pentazocine dihydroxynaphthyl acid

[0096] 1.36 g of dihydroxynaphthyl acid and 40 ml of isopropanol were added to a 50 ml reaction flask and heated to 55–60 °C. 1.0 g of pentazocine was slowly added, and the mixture was stirred for 30 min at this temperature. The mixture was then filtered to remove insoluble matter. The filtrate was slowly cooled to 20–25 °C, and granular solid precipitated. The mixture was stirred overnight, filtered, and the filter cake was dried under vacuum to obtain 1.19 g of a yellow amorphous solid, with a yield of 70.83%.

[0097] Example 12: Spectrum Analysis

[0098] Appendix Figure 3 The proton NMR spectrum of pentazocine dihydroxynaphthyl acid. 1 H-NMR (400MHz, DMSO / TMS, ppm):

[0099] Δδ10.84 (1H, s, -COOH); δ9.45 (1H, s, -COOH); δ8.31~8.25 (4H, m, dihydroxynaphthyl acid benzene ring); δ7.74~7.72 (2H, d, dihydroxynaphthyl acid benzene ring); δ7.21~7.17 (2H, t, dihydroxynaphthyl acid benzene ring); δ7.10~7.02 (4H, m, dihydroxynaphthyl acid and pentazocine benzene ring); δ6.77~6.69 (4H, m, dihydroxynaphthyl acid and pentazocine benzene ring); δ5.42~5.39 (2H, t, -CH=C-); δ4.77 (2H, s, Ph-CH2-Ph); δ3.86~3.73 (8H, m, phenolic hydroxyl group, -CH2-) ; δ3.21~2.98 (3H, m, -CH2-, -CH-) ; δ2.28~2.27 (2H, d, -CH-) ; δ2.08~2.02 (2H, t, -CH2-) ; δ1.79~1.76 (12H, d, -CH3) ; δ1.56~1.36 (8H, m, -CH2-); δ1.08~1.07 (7H, m,-CH 3、-CH-); δ0.87 ~0.85 (6H, d, -CH3);

[0100] Appendix Figure 4 Carbon spectrum of pentazocine dihydroxynaphthyl acid. 1 C-NMR (400MHz, DMSO / TMS, ppm):

[0101] 172.81,156.90,156.43,142.42,140.73,135.93,129.92,129.71,129.12,126.92,126.81,124.22,123.65,122.09,121.63,120.10,114.61,114.43,112.53,62.57,58.14,51.65,45.66,35.45,34.77,29.43,26.32,26.01,24.83,22.65,20.44,18.67,13.50;

[0102] Appendix Figure 6 DSC analysis of pentazocine dihydroxynaphthyl acid. This product undergoes a glass transition between 55.27℃ and 169.01℃.

[0103] Appendix Figure 5 TGA of pentazocine dihydroxynaphthyl acid. This product begins to melt and decompose at approximately 141.39°C;

[0104] Appendix Figure 1 XRD of pentazocine dihydroxynaphthyl acid. This product is amorphous; (Test conditions: XRD: performed on a Shimadzu 6100 diffractometer using Cu-Ka X-rays at a wavelength of 1.54 nm, 40 kV and 30 mA. The instrument was checked for performance using corundum before testing. The test sample was placed on a non-reflective plate at room temperature. Test conditions: scan range 5-90°, 10° / min).

[0105] Appendix Figure 7 IR of pentazocine dihydroxynaphthyl acid:

[0106] ;

[0107] Comparative Example 1: Preparation of Crystallized Pentazocine Dihydroxynaphthyl Acid

[0108] 500 mg of amorphous pentazocine dihydroxynaphthyl acid from Example 2 was dissolved in a mixture of 3 mL acetone and 0.5 mL water at 60 °C. The solution was slowly cooled to room temperature and stirred for 3 hours to obtain pentazocine dihydroxynaphthyl acid solid, which was collected, washed, and dried. The solid was characterized by XRPD, and the XRPD spectrum is attached. Figure 8 As shown. The analysis is as follows:

[0109] ;

[0110] From the appendix Figure 8 As can be seen, the pentazocine dihydroxynaphthyl acid prepared according to the method of Comparative Example 1 has obvious absorption peaks at 11.083, 11.563, 12.475, 16.912, and 17.236, indicating that the product obtained by this method is in crystalline form.

[0111] Comparative Example 2: Preparation of Pentazocine Dihydroxynaphthyl Acid

[0112] 0.68 g of dihydroxynaphthyl acid and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask and heated to 55–60 °C. 1.0 g of pentazocine was slowly added and dissolved. The mixture was kept warm and stirred for 30 min. After stirring, the mixture was concentrated to dryness, and 10 ml of propanol was added. The mixture was heated to reflux and dissolved. The temperature was slowly lowered to 0–5 °C for 6 h to crystallize. No solid precipitated. The mixture was then placed in a refrigerator and frozen overnight (-20 °C), resulting in the precipitation of an oily substance.

[0113] Comparative Example 3: Preparation of Pentazocine Dihydroxynaphthyl Acid

[0114] 0.68 g of dihydroxynaphthyl acid and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask and heated to 55–60 °C. 1.0 g of pentazocine was slowly added until dissolved, and the mixture was kept warm and stirred for 30 min. After stirring, the mixture was concentrated to dryness, and 30 ml of n-butanol was added. The mixture was heated to 70–80 °C until dissolved, and then slowly cooled to 20–25 °C. A viscous oily substance precipitated. The mixture was stirred overnight, and no change was observed.

[0115] Comparative Example 4: Preparation of Pentazocine Dihydroxynaphthyl Acid

[0116] 0.68 g of dihydroxynaphthyl acid and 20 ml of tetrahydrofuran were added to a 50 ml reaction flask and heated to 55–60 °C. 1.0 g of pentazocine was slowly added to dissolve the precipitate, and the mixture was stirred at this temperature for 30 min. After stirring, the mixture was concentrated to dryness, and 30 ml of acetonitrile was added. The mixture was heated to reflux, and the undissolved oily substance was removed by filtration. The filtrate was slowly cooled to 20–25 °C, and a viscous oily substance precipitated. The mixture was stirred overnight, and the oily substance at the bottom formed lumpy solids that adhered to the walls.

[0117] Comparative Example 5: Preparation of Pentazocine Dihydroxynaphthyl Acid

[0118] Add 0.68g of dihydroxynaphthyl acid and 20ml of N,N-dimethylformamide to a 50ml reaction flask, heat to 55-60℃, slowly add 1.0g of pentazocine, dissolve completely, and stir for 30min. Slowly cool to 0-5℃ and stir overnight until no solid precipitates.

[0119] Comparative Example 6: Preparation of Pentazocine Dihydroxynaphthyl Acid

[0120] Add 0.68g of dihydroxynaphthyl acid and 20ml of dioxane to a 50ml reaction flask, heat to 55-60℃, slowly add 1.0g of pentazocine, dissolve, and keep warm with stirring for 30min. Slowly cool to 0-5℃ and stir overnight, precipitating a viscous oily substance.

[0121] Comparative Example 7: Preparation of Pentazocine Dihydroxynaphthyl Acid

[0122] Add 0.68g of dihydroxynaphthyl acid and 20ml of N-methylpyrrolidone to a 50ml reaction flask, heat to 55-60℃, slowly add 1.0g of pentazocine, dissolve completely, and stir for 30min. Slowly cool to 0-5℃ and stir overnight until no solid precipitates.

[0123] Comparative Example 8: Preparation of Pentazocine Dihydroxynaphthyl Acid

[0124] Add 0.68g of dihydroxynaphthyl acid and 20ml of methyltetrahydrofuran to a 50ml reaction flask, heat to 55-60℃, slowly add 1.0g of pentazocine, dissolve, and keep warm with stirring for 30min. Slowly cool to 0-5℃ and stir overnight, precipitating a viscous oily substance.

[0125] Comparative Example 9: Preparation of Pentazocine Dihydroxynaphthyl Acid

[0126] Add 0.68g of dihydroxynaphthyl acid and 20ml of N,N-dimethylformamide to a 50ml reaction flask, heat to 55-60℃, slowly add 1.0g of pentazocine, dissolve completely, and stir for 30min while maintaining the temperature. Slowly add 20ml of isopropyl ether, cool to 20-25℃, and an oily substance will precipitate.

[0127] Comparative Example 10: Preparation of Pentazocine Dihydroxynaphthyl Acid

[0128] Add 0.68 g of dihydroxynaphthyl acid and 20 ml of dimethyl sulfoxide to a 50 ml reaction flask, heat to 55–60 °C, slowly add 1.0 g of pentazocine, dissolve completely, and stir for 30 min while maintaining the temperature. Slowly cool to 0–5 °C and stir overnight until no solid precipitates.

[0129] Solubility test:

[0130] This invention investigated the solubility (25°C) of pentazocine, pentazocine crystalline form (comparative Example 1), and amorphous pentazocine crystalline form in water. The specific experimental steps were as follows: pentazocine, pentazocine crystalline form, or amorphous pentazocine crystalline form were dissolved in water, 0.01 mol / L HCl solution, and pH 6.8 PBS to prepare the corresponding saturated solutions. The saturated solutions were then shaken in a 25°C water bath for 24 hours. After filtration, the content was determined by HPLC, and the corresponding solubility was calculated. The results are as follows:

[0131] ;

[0132] The results showed that the amorphous pentazocine dihydroxynaphthyl acid prepared in this invention had significantly lower solubility in water and other media compared with pentazocine base and pentazocine dihydroxynaphthyl acid crystals, demonstrating good low solubility characteristics. Its lower solubility can improve the stability and sustained-release effect of pentazocine dihydroxynaphthyl acid.

[0133] Preparation of pentazocine base solution in Comparative Examples 11, 12, and 13

[0134] ;

[0135] Preparation method: (1) Take the prescribed amount of pentazocine and add it to 90% of the oil in portions while stirring. After mixing, add oil to the full amount.

[0136] (2) Place the well-mixed initial suspension into a ball mill and grind it at 800 rpm. Grind for 3 minutes per cycle, stop for 5 minutes, and grind for a total of 5 cycles.

[0137] Comparative Example 14: Preparation of Pentazocine Suspension Injection

[0138] ;

[0139] Preparation method: Add the prescribed amount of pentazocine to an aqueous carrier and stir continuously to form a uniform paste. Then add the remaining carrier to bring the volume to a fixed level. Grind in a ball mill at 800 rpm for 3 minutes per cycle, followed by a 5-minute break, for a total of 5 cycles. Adjust the pH of the solution to 7.0–7.5 by adding lactic acid.

[0140] Examples 13, 14, 15, and 16: Preparation of aquatic suspensions of pentazocine dihydroxynaphthyl acid (amorphous)

[0141] ;

[0142] Preparation method: Accurately weigh the additive components and add them to water, stirring until dissolved. Adjust the pH to 7.4 with 1M NaOH aqueous solution. Accurately weigh pentazocine dihydroxynaphthyl acid and add it to the dispersion medium in small amounts several times at a rate of 200 rpm. After complete addition, continue stirring for 1 hour, and then grind using a media mill: the grinding media is 0.8 μm zirconia beads, the rotation speed is 2500 rpm, the pump speed is set to level 4, the air pressure is 4.0~4.5 bar, and the grinding time is 2 minutes. After grinding, dispense 1.0 mL of the ground suspension into each vial.

[0143] Examples 17 and 18: Preparation of lyophilized products of dihydroxynaphthyl pentazocine aqueous suspension

[0144] ;

[0145] Preparation method: Pentazocine dihydroxynaphthyl acid was added to the additive and homogenized using a high-speed homogenizer (15,000 rpm for 15 minutes) to achieve uniform dispersion. Particle size reduction was then achieved using a high-pressure homogenizer (5,000 PSI for 15 minutes, followed by 10,000 PSI for 15 minutes, then 15,000 PSI for 10 minutes). 3.2 mL of the suspension was lyophilized in a 5 mL vial and reconstituted with the initial volume of water. Observation showed that the formulation containing lactose as a cryoprotectant was easier to reconstitute than the formulation containing mannitol as a cryoprotectant.

[0146] Freeze-drying cycle:

[0147] ;

[0148] Example 19: Preparation of lyophilized product of pentazocine aqueous suspension

[0149] ;

[0150] Preparation method: Pentazocine dihydroxynaphthyl salt was added to the additive and homogenized using a high-speed homogenizer (15,000 rpm for 15 minutes) to achieve uniform dispersion. The dispersion was then subjected to a high-pressure homogenizer (5,000 PSI for 15 minutes, followed by 10,000 PSI for 15 minutes, then 15,000 PSI for 10 minutes) to reduce particle size. 3 mL of the suspension was dispensed into 5 mL vials and freeze-dried. After freeze-drying, it was reconstituted with the initial volume of water. The resulting freeze-dried block had an intact structure and could be reconstituted with the initial volume of water.

[0151] Freeze-drying cycle:

[0152] ;

[0153] Examples 20 and 21: Preparation of lyophilized products of dihydroxynaphthyl pentazocine aqueous suspension

[0154] ;

[0155] Preparation method: Povidone K12 was added to water for injection and stirred until completely dissolved. Then, Tween 80 and lactose were added sequentially under continuous stirring until completely dissolved, forming a homogeneous solution. Pentazocine dihydroxynaphthyl acid was added to the above solution, stirred to disperse, and then homogenized to achieve the desired particle size distribution. The final suspension was dispensed into 5 ml glass vials and lyophilized according to the lyophilization process parameters of Example 19. After lyophilization, the resulting lyophilized block was reconstituted using a mixed solution of sodium dihydrogen phosphate dihydrate and water.

[0156] Example 22: Pharmacokinetic Study in Rats

[0157] 1. In vivo high performance liquid chromatography analysis method

[0158] Chromatographic conditions: Octadecylsilane-bonded silica gel (4.6 × 100 mm; 2.6 μm) was used as the stationary phase; 15 mmol / L sodium borate (adjusted to pH 10.0 with 10 mol / L sodium hydroxide) was used as mobile phase A, and methanol was used as mobile phase B, with gradient elution; the flow rate was 0.5 mL / min; the column temperature was 40 °C; the detection wavelength was 225 nm; and the injection volume was 20 μL.

[0159] 2. Preparation of plasma samples

[0160] Blank plasma sample: Take blank plasma from rats, thaw it, and accurately measure 100µL into a 1.0mL centrifuge tube. Add 600µL of 4% glacial acetic acid methanol, vortex for 5 min, and centrifuge at 9000rpm for 10 min to precipitate proteins. Transfer the supernatant to a 1.0mL centrifuge tube and evaporate to dryness at 40℃. Redissolve the residue in methanol, vortex for 6 min, sonicate for 15 min, and centrifuge at 13000rpm for 20 min. The supernatant is the blank plasma sample solution.

[0161] Plasma samples after drug administration: After thawing, accurately measure 100 µL of rat plasma into a 1.0 mL centrifuge tube. Add 10 µL of internal standard metazocine (1 μg / mL, dissolved in methanol), and vortex for 1 min to mix thoroughly. Add 600 µL of 4% glacial acetic acid-methanol mixture, vortex for 5 min, and centrifuge at 9000 rpm for 1 min to precipitate proteins. Transfer the supernatant to a 1.0 mL centrifuge tube and evaporate to dryness at 40°C. Redissolve the residue in methanol, vortex for 6 min, sonicate for 15 min to ensure complete drug dissolution, and centrifuge at 13000 rpm for 20 min. The supernatant is the plasma sample solution after drug administration.

[0162] 3. Dosing regimen and sample collection

[0163] Thirty rats were randomly divided into five groups of six each. Each group received an intramuscular injection of the product described in Comparative Examples 14, 13, 14, 15, and 16 of this invention at a dosage of 125 mg / kg. Approximately 0.25 mL of blood was collected from the orbital vein of the rats at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 96, 144, 192, and 240 hours after administration. The blood was added to heparin-treated anticoagulant tubes, centrifuged at 4000 rpm for 10 min, and the supernatant plasma was separated and stored at -20°C for analysis.

[0164] 4. Plasma Sample Detection and Data Processing

[0165] Plasma samples were collected after drug administration and processed according to the method described in Section 2, "Preparation of Plasma Samples." The samples were injected under the chromatographic conditions described in Section 1, "In Vivo High Performance Liquid Chromatography Analysis Method." The peak area ratio of the active pharmaceutical ingredient to the internal standard peak was substituted into the standard curve to calculate the drug concentration. The results were processed using Phoenix software to calculate the relevant pharmacokinetic parameters.

[0166] 5. Results: See appendix Figure 9 .

[0167] The results show that the compounds of this invention can be slowly, continuously, and stably released in vivo and converted into pentazocine, thereby exerting a long-lasting effect. Simultaneously, the stable release achieves a long-lasting release effect.

[0168] Example 23: Pharmacokinetic Study in Beagle Dogs

[0169] Other treatment methods were the same as in Example 22, with male Beagle dogs receiving the formulations prepared according to Examples 20 and 21. Each group (N=6) received a single intramuscular injection of the formulation (equivalent to 20 mg / kg pentazocine). Blood samples were collected at predetermined time intervals to determine the pentazocine content. Results are attached. Figure 10 As shown, smaller particle size results in faster release from the body and higher concentration.

Claims

1. An amorphous product of pentazocine dihydroxynaphthyl acid, characterized in that, The dihydroxynaphthyl pentazocine has the structure shown in formula (I): ， Using Cu-Kα radiation, the X-ray powder diffraction pattern of the amorphous material is basically as shown in Figure 1.

2. A composition comprising the amorphous form of pentazocine dihydroxynaphthyl acid as described in claim 1.

3. The composition according to claim 2, wherein it is an injectable composition.

4. The composition according to claim 2 or 3, characterized in that, The composition provides extended release of pentazocine for at least 48 hours.

5. The composition according to claim 4, characterized in that, The particle size D90 of the amorphous form of pentazocine dihydroxynaphthyl acid is less than 50 micrometers.

6. The composition according to claim 4, characterized in that, The composition is prepared as an injection solution or lyophilized powder in liquid form.

7. The composition according to claim 2, characterized in that, The release of Zanzacin lasted for a month.

8. The composition according to claim 2, characterized in that, The amorphous particles of pentazocine dihydroxynaphthyl acid have a D90 of less than 30 micrometers, and the composition provides prolonged release of pentazocine.

9. The composition according to claim 8, characterized in that, The amorphous particles of pentazocine dihydroxynaphthyl acid have a particle size D90 of less than 15 micrometers, and the composition provides prolonged release of pentazocine.

10. The composition according to claim 9, characterized in that, The amorphous particles of pentazocine dihydroxynaphthyl acid have a particle size D90 of less than 10 micrometers, and the composition provides prolonged release of pentazocine.

11. The composition according to claim 7, characterized in that, The release time of pentazocine can last up to 7 days.

12. The composition according to claim 7, characterized in that, The release time of pentazocine can last up to 5 days.

13. Use of the amorphous form of pentazocine dihydroxynaphthyl acid according to claim 1 or the composition according to any one of claims 2-12 in the preparation of a medicament for acute and chronic pain.

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